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Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: A phase 1 dose-escalation trial
Abstract
The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC).
We did an open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion phase, both at the VU University Medical Centre (Amsterdam, Netherlands). Eligible patients had documented mCRPC and had not been previously treated with chemotherapy. All patients received a 5×10(8) cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3×10(8) cells every 2 weeks for 24 weeks. The vaccinations were combined with intravenous ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort received an escalating dose of ipilimumab at 0·3, 1·0, 3·0, or 5·0 mg/kg. Our primary endpoint was safety. This study is registered with ClinicalTrials.gov, number NCT01510288.
We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 3·0 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 5·0 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 3·0 mg/kg dose level, rather than enrol a further three patients at the 5·0 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis--all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1-2 events seen in all patients), fatigue (grade 1-2 in 20 patients, grade 3 in two), and pyrexia (grade 1-2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 3·0 mg/kg or 5·0 mg/kg ipilimumab.
GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and ipilimumab is warranted.
Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam.
... However, these approaches remain resource-intensive [8]. GVAX is another notable approach that utilized irradiated tumor cells modified to express soluble GM-CSF to stimulate antigen presenting cells and induce an anti-tumor response [9]. However, the difficulty to regulate the amount of soluble GM-CSF secreted resulted in increased myeloid-derived suppressor cell (MDSC) and impaired DC responses in patients [10]. ...
... The cytokine GM-CSF has been known to induce DC maturation and activation [25,26]. One of the earliest iterations was in the form of GVAX [9], followed by Sipuleucel-T [27], Talimogene laherparevec (T-VEC) [28], and many other ...
... The cytokine GM-CSF has been known to induce DC maturation and activation [25,26]. One of the earliest iterations was in the form of GVAX [9], followed by Sipuleucel-T [27], Talimogene laherparevec (T-VEC) [28], and many other approaches [29]. These approaches rely on the delivery of GM-CSF ex vivo to patient PBMCs, or the generalized production of GM-CSF into the periphery in the case of GVAX or T-VEC. ...
Dendritic cells (DCs) are the most effective antigen presenting cells for the development of T cell responses. The only FDA approved DC-based immunotherapy to date is Sipuleucel-T, which utilizes a fusion protein to stimulate DCs ex vivo with GM-CSF and simultaneously deliver the antigen PAP for prostate cancer. This approach is restricted by the breadth of immunity elicited to a single antigen, and to cancers that have a defined tumor associated antigen. Other multi-antigen approaches have been restricted by poor efficacy of vaccine adjuvants. We have developed a vaccine platform that consists of autologous DCs pulsed with cytokine-adjuvanted tumor membrane vesicles (TMVs) made from tumor tissue, that encapsulate the antigenic landscape of individual tumors. Here we test the efficacy of DCs pulsed with TMVs incorporated with glycolipid-anchored immunostimulatory molecules (GPI-ISMs) in HER2-positive and triple negative breast cancer murine models. Pulsing of DCs with TMVs containing GPI-ISMs results in superior uptake of vesicles, DC activation and cytokine production. Adaptive transfer of TMV-pulsed DCs to tumor bearing mice results in the inhibition of tumor growth, reduction in lung metastasis, and an increase in immune cell infiltration into the tumors. These observations suggest that DCs pulsed with TMVs containing GPI-GM-CSF and GPI-IL-12 can be further developed to be used as a personalized immunotherapy platform for cancer treatment.
... Ipilimumab, the ICI blocking the function of CTLA-4, started being tested in PCa clinical trials shortly after its FDA approval for the treatment of melanoma in 2011 [63,64]. Following encouraging results from phase I studies in patients with mCRPC, where it was shown that ipilimumab in combination with granulocyte macrophagecolony-stimulating factor (GM-CSF) in PCa vaccines induces significant PSA declines, an open-label phase I/II multicenter study (NCT00323882) investigating ipilimumab in patients with mCRPC, suggested clinical anti-tumor activity, as supported by manageable adverse events and sub-stantial disease control [65][66][67]. A subsequent phase III clinical trial (NCT00861614) found a significantly higher OS in mCRPC patients with favorable prognostic characteristics that received ipilimumab as compared to a placebo drug [59,68], with OS rates following a two to three times higher trend at three years onwards in cases where ipilimumab was administered along with radiotherapy [69]. ...
... and ipilimumab with GM-CSF[65], among many others. A signifi-cant number of clinical trials are currently ongoing or recruiting with the aim to investigate the efficacies of ICIS, both in monotherapy and in various therapeutic combinations; a list of ongoing studies is given inTable 1. www.videleaf.comTable ...
... Ipilimumab, the ICI blocking the function of CTLA-4, started being tested in PCa clinical trials shortly after its FDA approval for the treatment of melanoma in 2011 [63,64]. Following encouraging results from phase I studies in patients with mCRPC, where it was shown that ipilimumab in combination with granulocyte macrophagecolony-stimulating factor (GM-CSF) in PCa vaccines induces significant PSA declines, an open-label phase I/II multicenter study (NCT00323882) investigating ipilimumab in patients with mCRPC, suggested clinical anti-tumor activity, as supported by manageable adverse events and substantial disease control [65][66][67]. A subsequent phase III clinical trial (NCT00861614) found a significantly higher OS in mCRPC patients with favorable prognostic characteristics that received ipilimumab as compared to a placebo drug [59,68], with OS rates following a two to three times higher trend at three years onwards in cases where ipilimumab was administered along with radiotherapy [69]. ...
... In order to overcome therapeutic limitations, to enhance the therapeutic potential of ICIs and to extend the survival benefit to larger subsets of patients, many studies are currently investigating combinations of two different types of ICIs, or ICIs with other treatment modalities. Examples include combination regimens of nivolumab with ipilimumab [82][83][84], nivolumab with docetaxel [85], pembrolizumab with enzalutamide [86,87], and ipilimumab with GM-CSF [65], among many others. A significant number of clinical trials are currently ongoing or recruiting with the aim to investigate the efficacies of ICIS, both in monotherapy and in various therapeutic combinations; a list of ongoing studies is given in Table 1. ...
Simple Summary
Immunotherapy has emerged as an attractive alternative to conventional therapies for the clinical management of prostate cancer (PCa); it not only specifically targets malignant cells while protecting healthy tissue, but it also appears to augment the therapeutic effect of existing treatments when used in combination. The identification of biomarkers with prognostic and preventive clinical significance has facilitated the incorporation of immune-targeted agents in clinical trials, with the aim to assess therapeutic efficacy in patient sub-populations that have been stratified on the basis of specific molecular traits and prognostic variables. This perfectly fits the rationale of precision medicine, which aims to match patients with targeted therapies so as to achieve the maximum clinical benefit. The numerous clinical trials currently evaluating multiple immunotherapeutic approaches in PCa patients, both alone and in combination with other treatments, offer much hope for achieving significant advances in the decision for precision treatment of the disease.
Abstract
Prostate cancer (PCa) is the most frequently diagnosed type of cancer among Caucasian males over the age of 60 and is characterized by remarkable heterogeneity and clinical behavior, ranging from decades of indolence to highly lethal disease. Despite the significant progress in PCa systemic therapy, therapeutic response is usually transient, and invasive disease is associated with high mortality rates. Immunotherapy has emerged as an efficacious and non-toxic treatment alternative that perfectly fits the rationale of precision medicine, as it aims to treat patients on the basis of patient-specific, immune-targeted molecular traits, so as to achieve the maximum clinical benefit. Antibodies acting as immune checkpoint inhibitors and vaccines entailing tumor-specific antigens seem to be the most promising immunotherapeutic strategies in offering a significant survival advantage. Even though patients with localized disease and favorable prognostic characteristics seem to be the ones that markedly benefit from such interventions, there is substantial evidence to suggest that the survival benefit may also be extended to patients with more advanced disease. The identification of biomarkers that can be immunologically targeted in patients with disease progression is potentially amenable in this process and in achieving significant advances in the decision for precision treatment of PCa.
... GVAX is currently transitioning from Phase I to Phase II human clinical trials, with very encouraging results published in February 2012. A fixed dose of GVAX was conducted in conjunction with a dose escalation trial of Ipilimumab, a CTLA4-blocking antibody, for patients with metastatic castration-resistant prostate cancer (mCRPC) [31]. ...
Components of the TGF-β superfamily have been well established in their intricate and multifaceted roles in cancer progression and survival. The TGF-βs have been targeted therapeutically in an attempt to modify complex tumour networks to favour cancer cell destruction. Goals of these therapies are often to attack the "hallmarks" of cancer: characteristics acquired by cancer cells via rewiring or manipulating existing biological pathways to their survival advantage. Of the multitude of targeted therapies currently available, viral therapies have shown much promise in their efficacy of treatment. This review highlights current viral therapies targeting members of the TGF-β superfamily, with a focus on the strengths and limitations associated with this form of targeted cancer therapy.
... In a murine transgenic model of prostate cancer in which mice express the SV40 large T antigen under a prostate-specific promoter and develop spontaneous prostate tumours by 20 weeks of age, GVAX vaccination or cytotoxic T lymphocyte antigen 4 (CTLA4) blockade alone did not reduce tumour incidence, yet the combination of the two agents led to a reduction in prostate tumour incidence and inflammation within the prostate 40 . This approach was evaluated in a phase I dose-escalation trial, in which adverse events were more frequent with the combination therapy than those reported in clinical trials in which the single agents were used; however, 25% of patients had PSA declines of >50%, a higher frequency than previously reported for GVAX alone or CTLA4 blockade alone 41 . GVAX was also assessed in combination with androgen deprivation and cyclophosphamide in a trial including patients with newly diagnosed prostate cancer treated before prostatectomy 42 . ...
Prostate cancer is a leading cause of death in men worldwide. For over 30 years, growing interest has focused on the development of vaccines as treatments for prostate cancer, with the goal of using vaccines to activate immune cells capable of targeting prostate cancer to either eradicate recurrent disease or at least delay disease progression. This interest has been prompted by the prevalence and long natural history of the disease and by the fact that the prostate is an expendable organ. Thus, an immune response elicited by vaccination might not need to target the tumour uniquely but could theoretically target any prostate tissue. To date, different vaccine approaches and targets for prostate cancer have been evaluated in clinical trials. Overall, five approaches have been assessed in randomized phase III trials and sipuleucel-T was approved as a treatment for metastatic castration-resistant prostate cancer, being the only vaccine approved to date by the FDA as a treatment for cancer. Most vaccine approaches showed safety and some evidence of immunological activity but had poor clinical activity when used as monotherapies. However, increased activity has been observed when these vaccines were used in combination with other immune-modulating therapies. This evidence suggests that, in the future, prostate cancer vaccines might be used to activate and expand tumour-specific T cells as part of combination approaches with agents that target tumour-associated immune mechanisms of resistance.
... Similarly, a recently completed phase III trial using docetaxel with or without pembrolizumab (KEYNOTE-921) for patients with advanced prostate cancer showed no improvement in overall survival. Notwithstanding, earlier phase clinical trials have suggested that checkpoint blockade therapies may have efficacy in combination with other agents, including vaccines, and hence combination trials are being further pursued [78,79]. ...
Prostate cancer is the most diagnosed malignancy in men in the United States and the second leading cause of cancer-related death. For localized disease, radiation therapy is a standard treatment that is often curative. For metastatic disease, radiation therapy has been primarily used for palliation, however, several newer systemic radiation therapies have been demonstrated to significantly improve patient outcomes and improve survival. In particular, several targeted radionuclide therapies have been approved for the treatment of advanced-stage cancer, including strontium-89, samarium-153, and radium-223 for bone-metastatic disease, and lutetium-177-labeled PSMA-617 for patients with prostate-specific membrane antigen (PSMA)-expressing metastatic castration-resistant prostate cancer (mCRPC). Contrarily, immune-based treatments have generally demonstrated little activity in advanced prostate cancer, with the exception of the autologous cellular vaccine, sipuleucel-T. This has been attributed to the presence of an immune-suppressive prostate cancer microenvironment. The ability of radiation therapy to not only eradicate tumor cells but also potentially other immune-regulatory cells within the tumor immune microenvironment suggests that targeted radionuclide therapies may be well poised to combine with immune-targeted therapies to eliminate prostate cancer metastases more effectively. This review provides an overview of the recent advances of targeted radiation agents currently approved for prostate cancer, and those being investigated in combination with immunotherapy, and discusses the challenges as well as the opportunities in this field.
... Immune checkpoint inhibitors are not widely explored in terms of function and timing in prostate cancer. Nonetheless, they have been demonstrated to improve the efficacy of therapeutic vaccines when administered in a combined fashion [5][6][7]. The combination of immunotherapy with chemotherapy is also an option for generating antitumor immune reactivity and clinical efficacy, given that chemotherapeutic drugs (i) may circumvent tumor-induced immune suppression by counteracting immune suppressor circuits, and (ii) may stimulate robust antitumor immunity by inducing immunogenic cell death [8,9]. ...
During the last decade, there has been significant progress in the field of prostate cancer therapeutic treatments based on androgen receptor-axis-targeted therapies, which resulted in improved clinical outcomes [...]
... Studies suggest that this vaccination induces immune response through the activation of DCs and MDSCs [167]. A combinational therapy with ipilimumab has been investigated in a phase I trial by van den Eertwegh et al., which showed that GVAX is well-tolerated and safe for patients with mCRPC [168]. Once again, further clinical trials are required [169]. ...
Due to its slow progression and susceptibility to radical forms of treatment, low-grade PC is associated with high overall survival (OS). With the clinical progression of PC, the therapy is becoming more complex. The immunosuppressive tumor microenvironment (TME) makes PC a difficult target for most immunotherapeutics. Its general immune resistance is established by e.g., immune evasion through Treg cells, synthesis of immunosuppressive mediators, and the defective expression of surface neoantigens. The success of sipuleucel-T in clinical trials initiated several other clinical studies that specifically target the immune escape of tumors and eliminate the immunosuppressive properties of the TME. In the settings of PC treatment, this can be commonly achieved with radiation therapy (RT). In addition, focal therapies usually applied for localized PC, such as high-intensity focused ultrasound (HIFU) therapy, cryotherapy, photodynamic therapy (PDT), and irreversible electroporation (IRE) were shown to boost the anti-cancer response. Nevertheless, the present guidelines restrict their application to the context of a clinical trial or a prospective cohort study. This review explains how RT and focal therapies enhance the immune response. We also provide data supporting the combination of RT and focal treatments with immune therapies.
... In 12 chemotherapy-naive mCRPC patients, a phase I trial assessing the combination of ipilimumab and GVAX showed that the combination therapy resulted in a PSA decrease of ≥50 in 25% of patients with few side effects [115]. In another trial of 30 patients with mCRPC, the researchers evaluated the effects of ipilimumab and the PROSTVAC vaccination together. ...
In recent history, immunotherapy has become a viable cancer therapeutic option. However, over many years, its tenets have changed, and it now comprises a range of cancer-focused immunotherapies. Clinical trials are currently looking into monotherapies or combinations of medicines that include immune checkpoint inhibitors (ICI), CART cells, DNA vaccines targeting viruses, and adoptive cellular therapy. According to ongoing studies, the discipline should progress by incorporating patient-tailored immunotherapy, immune checkpoint blockers, other immunotherapeutic medications, hormone therapy, radiotherapy, and chemotherapy. Despite significantly increasing morbidity, immunotherapy can intensify the therapeutic effect and enhance immune responses. The findings for the immunotherapy treatment of advanced prostate cancer (PCa) are compiled in this study, showing that is possible to investigate the current state of immunotherapy, covering new findings, PCa treatment techniques, and research perspectives in the field’s unceasing evolution.
... Studies suggest that this vaccination induces the immune response by activation of DCs and MDSCs [131]. A combinational therapy with ipilimumab has been investigated in a phase I trial by van den Eertwegh et al., which showed that GVAX is welltolerated and safe for patients with mCRPC [132]. Once again, further clinical trials are required [133]. ...
Due to slow progression and susceptibility to radical forms of treatment low-grade PC is associ-ated with high overall survival (OS). With the clinical progression of PC the therapy is getting more complex. The immunosuppressive tumor microenvironment (TME) makes PC a difficult target for most immunotherapeutics. Its general immune resistance is established by i.e. immune evasion through Treg cells, synthesis of immunosuppressive mediators, and defective expression of surface neoantigens. The success of sipuleucel-T in clinical trials initiated several other clinical studies that specifically target the immune escape of the tumor and eliminate the immunosuppres-sive properties of TME. In the settings of PC treatment, this can be commonly achieved with radi-ation therapy (RT). Also, focal therapies usually applied for localized PC, such as high-intensity focused ultrasound (HIFU) therapy, cryotherapy, photodynamic therapy (PDT), or irreversible electroporation (IRE) were shown to boost anti-cancer response. Nevertheless, the present guide-lines restrict their application to localized and low-grade PC. This review explains how RT and focal therapies enhance the immune response. We also provide data supporting the combination of RT and focal treatments with immune therapies.
... In poorly immunogenic tumor models, the use of CTLA-4-blocking antibodies alone was not sufficient to improve patient survival/shrink tumor mass, but in combination with a DC vaccine, patients with melanoma had increased TILs, specific T cell responses, and clinical benefit in a pre-clinical trial [175]. An advanced form of a DC vaccine, GVAX (GM-CSF-transduced prostate cancer vaccine), gave clinical benefit and had a good safety profile when used in combination with ipilimumab (anti-CTLA-4 antibody) in a phase I dose-escalation trial [176]. Another form of DC vaccine, TriMix-DC (MoDCs electroporated with mRNA encoding CD70, CD40L, and TLR4), had a synergistic effect with ipilimumab in patients with advanced melanoma [177]. ...
Dendritic cells mediate innate and adaptive immune responses and are directly involved in the activation of cytotoxic T lymphocytes that kill tumor cells. Dendritic cell-based cancer immunotherapy has clinical benefits. Dendritic cell subsets are diverse, and tumors can be hot or cold, depending on their immunogenicity; this heterogeneity affects the success of dendritic cell-based immunotherapy. Here, we review the ontogeny of dendritic cells and dendritic cell subsets. We also review the characteristics of hot and cold tumors and briefly introduce therapeutic trials related to hot and cold tumors. Lastly, we discuss dendritic cell-based cancer immunotherapy in hot and cold tumors.
... The most frequently occurring AEs in groups that received combination therapies seemed to be fatigue, chills, diarrhea, pruritus, rash, colitis and endocrine events, which were all manageable and responded to steroids and hormone replacement. However, in trials that used GVAX, injection-site reactions and influenza-like illness were also reported as immunerelated AEs [68,69]. ...
Cancer vaccine efficacy is influenced by several factors, but one of the most important is the immunosuppressive tumor microenvironment, which can attenuate treatment effects. The combination of therapeutic cancer vaccines with other immunotherapies or conventional therapeutic approaches can promote vaccine efficacy by increasing immune surveillance and tumor immunogenicity and modulating immune escape in the tumor microenvironment. Inhibitory checkpoints have a significant role in the modulation of anticancer immune responses, and according to preclinical and clinical trials, administration of immune checkpoint inhibitors (ICIs) in combination with cancer vaccines can markedly improve their therapeutic effects, considering their low clinical efficacy. In addition, these combinatorial therapies have acceptable safety and minimal additional toxicity compared with single-agent cancer vaccines or ICIs. In this review, based on the results of previous studies, we introduce and discuss treatments that can be combined with therapeutic cancer vaccines to improve their potency. Our major focus is on checkpoint blockade therapies, which are the most well-known and applicable immunotherapies.
... Promising results were obtained in phase II clinical trial in prostate cancer patients, whereas phase III trial reported the inefficiency of GVAX or combination of GVAX with the chemotherapeutic agent to achieve survival benefit of metastatic CRPC. Hence, the trials were discontinued [35,36]. ...
Abstract
Cancer vaccines, also called therapeutic vaccines, improve the body's standard defense against cancer. Usually, the cancer vaccine is provided to the patient with already detected cancer. Immunotherapy is aimed more directly at cancer cells compared to conventional surgery, chemotherapy, or radiotherapy, offering patients the potential to provide improved reactions, enhance life-quality, or even cure the disease. Cancer vaccines might be designed to target tumor-associated antigens (TAAs), cancer germline antigens, virus-related antigens, or tumor-specific antigens (TSAs), which are also widely recognized as neoantigens. Sipuleucel-T (Provenge) and Talimogene laherparepvec (T-VEC) are the two FDA-approved vaccines currently being utilized for advanced prostate cancer and advanced melanoma skin cancer, respectively. Clinical trials are essential for learning more about cancer vaccines. Researchers are testing vaccines for several types of cancers, including bladder cancer, brain tumor, breast cancer, cervical cancer, colorectal cancer, lung cancer, and many more. This chapter discusses the literature and data on the value and use of cancer vaccines. Although cancer vaccines as a single therapy are not sufficient to declare a complete victory over this deadly disease until now, it must be a comprehensive approach and existing treatments on the concept of cancer management.
... A common type is tumor cell vaccines that are derived from cancerous cells. The tumor cells in the vaccine can be autologous i.e., derived from the patient themselves (Schulof et al., 1988;Harris et al., 2000;Berger et al., 2007) or allogenic i.e., derived from secondary human tumor cell lines (Sondak et al., 2006;Kelly and Giaccone, 2011;Wang et al., 2011;Van Den Eertwegh et al., 2012). Another common cell-based cancer vaccine is to use dendritic cells, which are often generated or modified ex vivo to be injected into cancer patients (Inaba et al., 1992;Rosenblatt et al., 2011;Guo et al., 2012). ...
Immunotherapy is becoming a very common treatment for cancer, using approaches like checkpoint inhibition, T cell transfer therapy, monoclonal antibodies and cancer vaccination. However, these approaches involve high doses of immune therapeutics with problematic side effects. A promising approach to reducing the dose of immunotherapeutic agents given to a cancer patient is to combine it with electrical stimulation, which can act in two ways; it can either modulate the immune system to produce the immune cytokines and agents in the patient’s body or it can increase the cellular uptake of these immune agents via electroporation. Electrical stimulation in form of direct current has been shown to reduce tumor sizes in immune-competent mice while having no effect on tumor sizes in immune-deficient mice. Several studies have used nano-pulsed electrical stimulations to activate the immune system and drive it against tumor cells. This approach has been utilized for different types of cancers, like fibrosarcoma, hepatocellular carcinoma, human papillomavirus etc. Another common approach is to combine electrochemotherapy with immune modulation, either by inducing immunogenic cell death or injecting immunostimulants that increase the effectiveness of the treatments. Several therapies utilize electroporation to deliver immunostimulants (like genes encoded with cytokine producing sequences, cancer specific antigens or fragments of anti-tumor toxins) more effectively. Lastly, electrical stimulation of the vagus nerve can trigger production and activation of anti-tumor immune cells and immune reactions. Hence, the use of electrical stimulation to modulate the immune system in different ways can be a promising approach to treat cancer.
... Given that immunotherapy moves toward combinational regimens, including ICPi, further exploration of ir thyroid disorders in this setting is required. So far, the combination of different classes of ICPi has been shown to increase endocrine toxicity [30,31,43], though inconsistently [41], while combining ICPi with other anticancer agent results in variable endocrine toxicity [154][155][156][157][158][159][160][161]. ...
Background:
Until more data are available to shed light on the thyroid disorders related to immune checkpoint inhibitors (ICPi) implemented for the treatment of hematological malignancies, the decision-making is guided by pertinent data derived mostly from solid tumors.
Methods:
The present review provides a comprehensive and updated overview of the thyroid disorders related to ICPi, namely to inhibitors of cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death (PD) 1 (PD-1), and the ligand of the latter (PD-L1).
Results:
With the increasing recognition of ir thyroid disorders, many outstanding issues have emerged. Ir thyroid disorders are reminiscent of, but not identical to, thyroid autoimmunity. Interclass and intraclass ICPi differences regarding thyroid immunotoxicity await interpretation. The available data concerning the predictive value of thyroid autoantibodies for the development of ir thyroid disorders are inconclusive. Mounting data indicate an association of ir thyroid disorders with ICPi efficacy, but a causative link is still lacking. The path forward is a tailored approach, entailing: (i) the validation of tumor-specific, patient-specific, and ICPi-specific predictive factors; (ii) appropriate patient selection; (iii) the uncoupling of antitumor immunity from immunotoxicity; (iv) a multidisciplinary initiative; and (v) global registry strategies.
Conclusions:
Untangling and harnessing the interrelationship of immuno-oncology with endocrinology underlying the ir thyroid disorders will yield the optimal patient care.
... The most frequent ICI associated with sarcoid-like reactions in respiratory system is ipilimumab. This inhibitor of cytotoxic T lymphocyte antigen (CTLA)-4 has been correlated with granulomatous lesion in lungs, pleura and intrathoracic lymph nodes [67,[69][70][71][72][73][74][75][76][77]. In addition, sarcoid-like reactions in lungs and intrathoracic lymph nodes can occur in the setting of combination of cancer immunotherapies [78,79]. ...
Cancer immunotherapy aims to stimulate the immune system to fight against tumors, utilizing the presentation of molecules on the surface of the malignant cells that can be recognized by the antibodies of the immune system. Immune checkpoint inhibitors, a type of cancer immunotherapy, are broadly used in different types of cancer, improving patients' survival and quality of life. However, treatment with these agents causes immune-related toxicities affecting many organs. The most frequent pulmonary adverse event is pneumonitis representing a non-infective inflammation localized to the interstitium and alveoli. Other lung toxicities include airway disease, pulmonary vasculitis, sarcoid-like reactions, infections, pleural effusions, pulmonary nodules, diaphragm myositis and allergic bronchopulmonary aspergillosis. This review aims to summarize these pulmonary adverse events, underlining the significance of an optimal expeditious diagnosis and management.
... A current study is examining the effect of a neoantigen DNA vaccine in combination with PROSTVAC, nivolumab and ipilimumab (NCT03532217). Another trial is evaluating ipilimumab in combination with GVAX [94]. Pembrolizumab combination therapies in mCRPC are be-ing investigated in KEYNOTE-365 (NCT02861573) a phase Ib/II study mentioned in the previous section with four different study medications (pembrolizumab, docetaxel, enzalutamide, Olaparib, abiraterone and prednisone). ...
The use of immunotherapy has become a critical treatment modality in many advanced cancers. However, immunotherapy in prostate cancer has not been met with similar success. Multiple interrelated mechanisms, such as low tumor mutational burden, immunosuppressive cells, and impaired cellular immunity, appear to subvert the immune system, creating an immunosuppressive tumor microenvironment and leading to lower treatment efficacy in advanced prostate cancer. The lethality of metastatic castrate-resistant prostate cancer is driven by the lack of therapeutic regimens capable of generating durable responses. Multiple strategies are currently being tested to overcome immune resistance including combining various classes of treatment modalities. Several completed and ongoing trials have shown that combining vaccines or checkpoint inhibitors with hormonal therapy, radiotherapy, antibody–drug conjugates, chimeric antigen receptor T cell therapy, or chemotherapy may enhance immune responses and induce long-lasting clinical responses without significant toxicity. Here, we review the current state of immunotherapy for prostate cancer, as well as tumor-specific mechanisms underlying therapeutic resistance, with a comprehensive look at the current preclinical and clinical immunotherapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and impaired cellular immunity that have largely limited the utility of immunotherapy in advanced prostate cancer.
... Finally, ipilimumab has been also tested in combination with ARPIs (NCT01688492), sipuleucel-T [78], vaccines [79], and evofosfamide, an investigational hypoxia-activated prodrug that can potentially reduce hypoxia in the tumor microenvironment (TME) and improve the efficacy of ICIs (NCT03098160) (Tables 1 and 2). ...
Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC.
... This supports advancing novel therapeutic strategies for improving management of PCa. Several recent studies suggest that immunotherapy for the induction of immune responses in PCa is among a handful of highly promising therapeutic strategies to be further advanced [5][6][7]. The determination of suitable antigens with expression confined to relevant tumors and www.genesandcancer.com ...
Prostate cancer is a prevalent cancer in men and consists of both indolent and aggressive phenotypes. While active surveillance is recommended for the former, current treatments for the latter include surgery, radiation, chemo and hormonal therapy. It has been observed that the recurrence in the treated patients is high and results in castration resistant prostate cancer for which treatment options are limited. This scenario has prompted us to consider immunotherapy with synthetic DNA vaccines, as this approach can generate antigen-specific tumor-killing immune cells. Given the multifocal and heterogeneous nature of prostate cancer, we hypothesized that synthetic DNA vaccines targeting different prostate specific antigens are likely to induce broader and improved immunity who are at high risk as well as advanced clinical stage of prostate cancer, compared to a single antigen approach. Utilizing a bioinformatics approach, synthetic enhanced DNA vaccine (SEV) constructs were generated against STEAP1, PAP, PARM1, PSCA, PCTA and PSP94. Synthetic enhanced vaccines for prostate cancer antigens were shown to elicit antigen-specific immune responses in mice and the anti-tumor activity was evident in a prostate tumor challenge mouse model. These studies support further evaluation of the DNA tools for immunotherapy of prostate cancer and perhaps other cancers.
... Although early phase I/II clinical trials of ipilimumab in HRPC have shown promising results with reduced cancer growth in some patients, phase III trials failed to demonstrate OS benefit [32,73,77]. Combination of ipilimumab with other therapies like docetaxel, radiotherapy, ADT, PROSTVAC, GVAX, GM-CSF resulted in PSA decline of >50% in 16% to 50% of the treated cohort, also suggesting irrelevant clinical benefit [28,29,[78][79][80]. There was also no significant change in PSA doubling time when the tremelimumab was combined with ADT [81]. ...
Emerging research demonstrates that co-inhibitory immune checkpoints (ICs) remain the most promising immunotherapy targets in various malignancies. Nonetheless, ICIs have offered insignificant clinical benefits in the treatment of advanced prostate cancer (PCa) especially when they are used as monotherapies. Current existing PCa treatment initially offers an improved clinical outcome and overall survival (OS), however, after a while the treatment becomes resistant leading to aggressive and uncontrolled disease associated with increased mortality and morbidity. Concurrent combination of the ICIs with radionuclides therapy that has rapidly emerged as safe and effective targeted approach for treating PCa patients may shift the paradigm of PCa treatment. Here, we provide an overview of the contextual contribution of old and new emerging inhibitory ICs in PCa, preclinical and clinical studies supporting the use of these ICs in treating PCa patients. Furthermore, we will also describe the potential of using a combinatory approach of ICIs and radionuclides therapy in treating PCa patients to enhance efficacy, durable cancer control and OS. The inhibitory ICs considered in this review are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1), V-domain immunoglobulin suppressor of T cell activation (VISTA), indoleamine 2,3-dioxygenase (IDO), T cell Immunoglobulin Domain and Mucin Domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), B7 homolog 3 (B7-H3) and B7-H4.
... DCs move to the lymph nodes (LN), where the complex of peptide and MHC-class II is presented to the antigen-specific T-cell receptor (TCR) on the naive CD4 + T-cell. This again indicates the enhanced DCs function in tumor patients (150). ...
It is well known that hydrostatic pressure (HP) is a physical parameter that is now regarded as an important variable for life. High hydrostatic pressure (HHP) technology has influenced biological systems for more than 100 years. Food and bioscience researchers have shown great interest in HHP technology over the past few decades. The development of knowledge related to this area can better facilitate the application of HHP in the life sciences. Furthermore, new applications for HHP may come from these current studies, particularly in tumor vaccines. Currently, cancer recurrence and metastasis continue to pose a serious threat to human health. The limited efficacy of conventional treatments has led to the need for breakthroughs in immunotherapy and other related areas. Research into tumor vaccines is providing new insights for cancer treatment. The purpose of this review is to present the main findings reported thus far in the relevant scientific literature, focusing on knowledge related to HHP technology and tumor vaccines, and to demonstrate the potential of applying HHP technology to tumor vaccine development.
... It has been tested in two phase III trials, VITAL-1 and VITAL-2, and failed to show clinical benefit [68][69][70]. There are attempts to improve the efficacy of GVAX-PCa by combining it with CPIs [71]. ...
Simple Summary
Immunotherapy has changed the treatment paradigm of numerous malignancies such as non-small cell lung cancer and melanoma. To date, there has been only modest demonstrable efficacy of immunotherapy for prostate cancer. This lack of efficacy is likely due to the immunosuppressive tumor microenvironment. When we consider the fact that metastatic castrate-resistant state is the most lethal form of prostate cancer, there is an unmet need to increase the efficacy of immune therapies for this disease. The treatment paradigm has now shifted towards combinatorial regimens to enhance the anti-tumor immune response. These combinations with immunomodulatory agents in ongoing clinical trials include conventional agents such as chemotherapy and numerous novel agents. This review summarizes the clinical trials recruiting patients with metastatic castrate-resistant prostate cancer utilizing immunotherapeutic approaches.
Abstract
Although most prostate cancers are localized, and the majority are curable, recurrences occur in approximately 35% of men. Among patients with prostate-specific antigen (PSA) recurrence and PSA doubling time (PSADT) less than 15 months after radical prostatectomy, prostate cancer accounted for approximately 90% of the deaths by 15 years after recurrence. An immunosuppressive tumor microenvironment (TME) and impaired cellular immunity are likely largely responsible for the limited utility of checkpoint inhibitors (CPIs) in advanced prostate cancer compared with other tumor types. Thus, for immunologically “cold” malignancies such as prostate cancer, clinical trial development has pivoted towards novel approaches to enhance immune responses. Numerous clinical trials are currently evaluating combination immunomodulatory strategies incorporating vaccine-based therapies, checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells. Other trials evaluate the efficacy and safety of these immunomodulatory agents’ combinations with standard approaches such as androgen deprivation therapy (ADT), taxane-based chemotherapy, radiotherapy, and targeted therapies such as tyrosine kinase inhibitors (TKI) and poly ADP ribose polymerase (PARP) inhibitors. Here, we will review promising immunotherapies in development and ongoing trials for metastatic castration-resistant prostate cancer (mCRPC). These novel trials will build on past experiences and promise to usher a new era to treat patients with mCRPC.
... A phase I study of 30 mCRPC patients, of whom 24 were chemotherapy-naïve, did not identify any dose-limiting toxic effects upon treatment with escalating doses of ipilimumab in combination with a fixed dose of PROSTVAC [20]. Additional phase I and I/ II studies of mCRPC patients further confirmed the clinical potential of ipilimumab treatment, with common grade 3 or 4 immune-related AEs of diarrhea, colitis, rash, and hepatitis [20][21][22]. Based on these findings, the phase III CA184-043 trial was initiated to assess the efficacy of ipilimumab after radiotherapy in mCRPC patients who had progressed on docetaxel. ...
Immunotherapies have shown remarkable success in the treatment of multiple cancer types; however, despite encouraging preclinical activity, registration trials of immunotherapy in prostate cancer have largely been unsuccessful. Sipuleucel-T remains the only approved immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer based on modest improvement in overall survival. This immune evasion in the case of prostate cancer has been attributed to tumor-intrinsic factors, an immunosuppressive tumor microenvironment, and host factors, which ultimately make it an inert ‘cold’ tumor. Recently, multiple approaches have been investigated to turn prostate cancer into a ‘hot’ tumor. Antibodies directed against programmed cell death protein 1 have a tumor agnostic approval for a small minority of patients with microsatellite instability-high or mismatch repair-deficient metastatic prostate cancer. Herein, we present an overview of the current immunotherapy landscape in metastatic castration-resistant prostate cancer with a focus on immune checkpoint inhibitors. We describe the results of clinical trials of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer; either as single agents or in combination with other checkpoint inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, tyrosine kinase inhibitors, novel hormonal therapies, chemotherapies, and radioligands. Finally, we review upcoming immunotherapies, including novel monoclonal antibodies, chimeric-antigen receptor (CAR) T cells, Bi-Specific T cell Engagers (BiTEs), therapies targeting the adenosine pathway, and other miscellaneous agents.
With the successful development of immune checkpoint blockade, there remains the continued need to improve efficacy and decrease toxicities. The addition of GM-CSF to ipilimumab has previously demonstrated both an improvement in efficacy and decrease in the incidence of high-grade adverse events. ICOS+CD4+ or ICOS+CD8+ peripheral blood T cells are significantly greater in the patients treated with ipilimumab plus GM-CSF than in the patients treated with ipilimumab alone. To better understand the effects of GM-CSF on ICOS and clinical outcomes, the relative roles of identified soluble ICOS and membrane-bound ICOS were evaluated. The ICOS splice variant was secreted and found to have immunologic suppressive effects. Changes in soluble ICOS splice variant levels in treated patients correlated with clinical outcomes. GM-CSF enhanced membrane-bound ICOS in an IL12-dependent manner but did not increase soluble ICOS levels. Whereas soluble ICOS plays a role in immune suppression, GM-CSF efficacy involves increasing membrane-bound ICOS and induction of dendritic cell development. Thus, soluble ICOS splice variants may be used as a biomarker for GM-CSF and immune checkpoint blockade-based therapies.
Objective:
To describe the frequency of hypophysitis and hypopituitarism in cancer patients who are undergoing antineoplastic treatment with immunotherapy, as well as to describe the clinical, epidemiological, and demographic characteristics of these patients.
Methods:
A systematic search of the literature in PubMed, Embase, Web of Science, ClinicalTrials.gov and Cochrane Controlled Register of Trials took place on May 8 and 9, 2020. Randomized and nonrandomized clinical trials, cohort studies, case-control studies, case series and case reports were included.
Results:
A total of 239 articles were obtained, in which 963 cases of hypophysitis and 128 cases of hypopituitarism were found in a treated population of 30,014 individuals (3.20% and 0.42% of the evaluated population, respectively). In the cohort studies, the incidence of hypophysitis and hypopituitarism ranged from 0% to 27.59% and from 0% to 17.86%, respectively. In the non-randomized clinical trials, the incidence of hypophysitis and hypopituitarism ranged from 0% to 25% and from 0% to 14.67%, and in randomized clinical trials from 0% to 16.2% and from 0% to 33.33%. The most common hormonal changes were in the corticotrophic, thyrotrophic and gonadotrophic axes. The main magnetic resonance imaging (MRI) findings were enlargement of the pituitary gland and enhanced contrast uptake. The main symptoms presented by patients with hypophysitis were fatigue and headache.
Conclusion:
The present review reported a frequency of hypophysitis and hypopituitarism of 3.20% and 0.42%, respectively, in the evaluated population. The clinical-epidemiological characteristics of patients affected by hypophysitis were also described.
Systematic review registration:
https://www.crd.york.ac.uk/prospero/, identifier CRD42020175864.
Prostate cancer (PCa) is one of the most common cancers in the male population. Its incidence, mortality, and prevalence are different across different geographical areas, depending on the different approaches adopted for screening, early diagnosis, and availability of treatments. Digital rectal exploration (DRE) and the prostate-specific antigen (PSA) test are the most common clinical procedure used for PCa screening. The choice of treatment should be patient specific and risk adjusted. The therapeutic approaches for patients with PCa include different options: watchful waiting, radical prostatectomy, radiotherapy, hormone therapy, chemotherapy, immunotherapy, and treatment of bone metastases.
Prostate cancer (PC) is the most prevalent male urogenital cancer worldwide. PC patients presenting an advanced or metastatic cancer succumb to the disease, even after therapeutic interventions including radiotherapy, surgery, androgen deprivation therapy (ADT), and chemotherapy. One of the hallmarks of PC is evading immune surveillance and chronic inflammation, which is a major challenge towards designing effective therapeutic formulations against PC. Chronic inflammation in PC is often characterized by tumor microenvironment alterations, epithelial mesenchymal transition and extracellular matrix modifications. The inflammatory events are modulated by reactive nitrogen and oxygen species, inflammatory cytokines and chemokines. Major signaling pathways in PC includes androgen receptor, PI3K and NF-κB pathways and targeting these inter-linked pathways poses a major therapeutic challenge. Notably, many conventional treatments are clinically unsuccessful, due to lack of targetability and poor bioavailability of the therapeutics, untoward toxicity and multidrug resistance. The past decade witnessed an advancement of nanotechnology as an excellent therapeutic paradigm for PC therapy. Modern nanovectorization strategies such as stimuli-responsive and active PC targeting carriers offer controlled release patterns and superior anti-cancer effects. The current review initially describes the classification, inflammatory triggers and major inflammatory pathways of PC, various PC treatment strategies and their limitations. Subsequently, recent advancement in combinatorial nanotherapeutic approaches, which target PC inflammatory pathways, and the mechanism of action are discussed. Besides, the current clinical status and prospects of PC homing nanovectorization, and major challenges to be addressed towards the advancement PC therapy are also addressed.
The aim of this research is to use bibliometric analysis to investigate the status and patterns of the 100 most frequently cited publications regarding the Cytotoxic T-Lymphocyte-Associated Protein (CTLA-4) research for cancer. The articles published on the topic were retrieved from the core collection database of Web of Science and PubMed using the Medical Subject Heading (MeSH) of “CTLA-4” from 1986 to December 6, 2020. The selected articles were examined and the bibliometric data compiled based on the number of citations, the author’s name, journal, publication year, institution, country, and co-occurrence keywords. 4,874 eligible papers were returned from the Web of Science Core Collection Database and PubMed. The citation frequency ranged from 2372 to 205, with a median of 460, and the top cited paper had 2372 citations. The journals with the most papers were Cell (n = 8, 3541 citations, Impact Factor (IF) = 41.577) and Journal of Experimental Medicine (n = 7, 2716 citations, IF = 10.790). Most of the published papers were from the United States of America (USA) (41.8%). A total of 485 institutes and 29 countries were involved in these 100 articles. There were 1192 authors and the author with the highest number of papers was the Nobel Prize winner, Professor James P. Allison (17 papers; 8700 citations). CTLA-4 Blockade was the most frequent keyword (42.1%), followed by Metastatic Melanoma (4.26%). This work presents an important bibliographic source and can be saved as a reference for future medical health research on the function of CTLA-4 in cancer immunotherapy.
In recent years, the use of immune checkpoint inhibitors (ICIs) in combination with
approved or experimental vaccines has proven to be a promising approach to improve vaccine immunogenicity and efficacy. This strategy seeks to overcome the immunosuppressive mechanisms associated with the vaccine response, thereby achieving increased immunogenicity and efficacy. Most of the information on the use of ICIs combined with vaccines derives from studies on certain antitumor vaccines combined with monoclonal antibodies (mAbs) against either cytotoxic T lymphocyte associated
protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death-ligand
1 (PD-L1). However, over the past few years, emerging strategies to use new-generation ICIs as molecular adjuvants are paving the way for future advances in vaccine research. Here, we review the current state and future directions of the use of ICIs in experimental and clinical settings, including mAbs and alternative new approaches using antisense oligonucleotides (ASOs), small non-coding RNAs, aptamers, peptides, and other small molecules for improving vaccine efficacy. The scope of this review mainly includes the use of ICIs in therapeutic antitumor vaccines, although recent research on anti-infective vaccines will also be addressed.
In recent years, the use of immune checkpoint inhibitors (ICIs) in combination with approved or experimental vaccines has proven to be a promising approach to improve vaccine immunogenicity and efficacy. This strategy seeks to overcome the immunosuppressive mechanisms associated with the vaccine response, thereby achieving increased immunogenicity and efficacy. Most of the information on the use of ICIs combined with vaccines derives from studies on certain anti-tumor vaccines combined with monoclonal antibodies (mAbs) against either cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed death-ligand 1 (PD-L1). However, over the past few years, emerging strategies to use new-generation ICIs as molecular adjuvants are paving the way for future advances in vaccine research. Here, we review the current state and future directions of the use of ICIs in experimental and clinical settings, including mAbs and alternative new approaches using antisense oligonucleotides (ASOs), small non-coding RNAs, aptamers, peptides, and other small molecules for improving vaccine efficacy. The scope of this review mainly includes the use of ICIs in therapeutic antitumor vaccines, although recent research on anti-infective vaccines will also be addressed.
We present the case of a 50‐year‐old male patient with metastatic clear cell renal cell carcinoma (mRCC) who developed a diffuse pulmonary opacification and lymphadenopathy during nivolumab maintenance therapy. This was diagnosed as presumed sarcoid granulomatous inflammatory reaction secondary to immunotherapy, which resolved with holding off therapy and the nivolumab was resumed. We report a unique case of an immunotherapy‐induced sarcoid‐like reaction in the treatment of metastatic renal cell carcinoma. It is imperative that clinicians are aware these reactions often phenotypically resemble metastasis or disease progression and it may otherwise result in an unwarranted interruption of cancer treatment.
The creation of cancer vaccines is a constant priority for research and biotechnology. Therefore, the emergence of any new technology in this field is a significant event, especially because previous technologies have not yielded results. Recently, the development of a cancer vaccine has been complemented by a new proteomics technology platform that allows the creation of antigen compositions known as antigenic essences. Antigenic essence comprises a target fraction of cellular antigens, the composition of which is precisely controlled by peptide mass spectrometry and compared to the proteomic footprint of the target cells to ensure similarity. This proteomics platform offers potential for a massive upgrade of conventional cellular cancer vaccines. Antigenic essences have the same mechanism of action, but without the disadvantages, and with notable advantages such as precise targeting of the immune response, safety, controlled composition, improved immunogenicity, addressed MHC restriction, and extended range of vaccination doses. The present paper calls attention to this novel platform, stimulates discussion of the role of antigenic essence in vaccine development, and consolidates academic science with biotech capabilities. A brief description of the platform, list of cellular cancer vaccines suitable for the upgrade, main recommendations, limitations, and legal and ethical aspects of vaccine upgrade are reported here.
The immune checkpoint cytotoxic T lymphocyte-associated antigen 4 (CTLA-4 or CD152) is a negative regulator of T-cell-mediated immune responses which plays a critical role in suppressing autoimmunity and maintaining immune homeostasis. Because of its inhibitory activity on T cells, CTLA-4 has been investigated as a drug target to induce immunostimulation, blocking the interaction with its ligands. The antitumor effects mediated by CTLA-4 blockade have been attributed to a sustained active immune response against cancer cells, due to the release of a brake on T cell activation. Ipilimumab (Yervoy, Bristol-Myers Squibb) is a fully human anti-CTLA-4 IgG1κ monoclonal antibody (mAb) that represents the first immune checkpoint inhibitor approved as monotherapy by FDA and EMA in 2011 for the treatment of unresectable/metastatic melanoma. In 2015, FDA also granted approval to ipilimumab monotherapy as adjuvant treatment of stage III melanoma to reduce the risk of tumour recurrence. The subsequent approved indications of ipilimumab for metastatic melanoma, regardless of BRAF mutational status, and other advanced/metastatic solid tumours always involve its use in association with the anti-programmed cell death protein 1 (PD-1) mAb nivolumab. Currently, ipilimumab is evaluated in ongoing clinical trials for refractory/advanced solid tumours mainly in combination with additional immunostimulating agents.
Context
Therapies based on immune checkpoint inhibitors (ICIs) are transforming the treatment landscape of urologic oncology. Nevertheless, an exhaustive overview of the toxicity spectrum of these novel therapies has yet to be provided.
Objective
To comprehensively investigate the incidence and profile of ICI therapy-related adverse events (AEs) across urologic cancers.
Evidence acquisition
We searched for all clinical trials investigating the role of ICI therapy published between January 2010 and September 2021. Studies involving urologic cancers with reported overall incidence or tabulated data of treatment-related AEs (trAEs) or immune-related AEs (irAEs) were included. A systematic review and meta-analysis was performed after protocol registration in PROSPERO (CRD42021276435).
Evidence synthesis
We identified 2638 records, of which 92 studies (including 22 942 participants) met the inclusion criteria. The pooled overall incidence was 81.6% (95% confidence interval [CI] 78.0–84.7) for any-grade trAEs and 29.3% (95% CI 24.9–34.1) for grade ≥3 trAEs. The pooled overall incidence was 34.3% (95% CI 28.5–40.7) for any-grade irAEs and 10.2% (95%CI 8.2–12.7) for grade ≥3 irAEs. On a multivariable analysis, cancer type, therapy combination, clinical settings (perioperative vs advanced/metastatic), and drug exposure were independently associated with the occurrence of trAEs or irAEs. The overall rate of treatment-related mortality was 0.94% (140 of 14 899 participants), with pneumonitis (9.3%), pneumonia (7.9%), and respiratory failure (7.1%) being the most common causes. Immune-related mortality occurred in 0.26% (28 of 10 723) patients, with pneumonitis (35.7%), hepatic failure (10.7%), and hepatitis (7.1%) being most common.
Conclusions
Our study provides a comprehensive overview of ICI-associated AEs in urologic cancer patients. The spectrum and incidence of AEs vary across cancer types, ICI types, clinical settings, and therapy combinations. These findings provide important guidance to clinicians in counseling and management of patients with urologic cancers.
Patient summary
A high proportion of patients experience immune checkpoint inhibitor–associated toxicity. Physician and patient education is critical for early recognition and proper management.
Introduction
Medical treatment for prostate cancer (PC) targets hormonal pathways used by malignant cells. Research advances aided in gaining knowledge about implicated molecular pathways and opened the way for establishment of new types of therapies by modifying immunological mechanisms. The aim of this review is to present completed and ongoing research projects regarding PC immunotherapy.
Areas covered
A literature search was conducted in PubMed/MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, and https://www.clinicaltrials.gov/ from inception until 07/2021, to identify completed or ongoing Phase III trials regarding several immunotherapies against PC. Studies on vaccine therapies, CTLA-4 inhibitors, PD-1/PD-L1 inhibitors, PARP inhibitors, PSMA-targeted therapies, and tyrosine kinase inhibitors were considered eligible.
Expert opinion
Although many molecules are being tested against PC cells, only sipuleucel-T has gain approval in the USA. The main reason for this delay in establishing immunotherapy as a standard option for managing PC is the heterogeneity and tumor immune microenvironment complexities. Ipilimumab and olaparib were proved to prolong overall survival significantly against placebo, but a lot of research is going on to identify which patients and at what stage of disease will benefit the most before incorporating them in clinical practice. More recent options such as PSMA-targeted treatments are currently evaluated.
Article Highlights
• Intense research performed on immunotherapy for prostate cancer.
• Vaccine therapy with sipuleucel-T, the only approved immunotherapy for prostate cancer.
• Ipilimumab shows survival benefits.
• Olaparib shows survival benefits.
• Findings should be confirmed on further trials to identify target population characteristics and proper disease stage.
• Immunotherapy is not yet a standard due to tumor environment complex interaction between immune system and malignant cells.
The use of immune checkpoint inhibitors (ICI) has substantially increased the overall survival of cancer patients and has revolutionized the therapeutic situation in oncology. However, not all patients and cancer types respond to ICI, or become resistant over time. Combining ICIs with therapeutic cancer vaccines is a promising option as vaccination may help to overcome resistance to immunotherapies while immunotherapies may increase immune responses to the particular cancer vaccine by reinvigorating exhausted T cells. Thus, it would be possible to reprogram a response with appropriate vaccines, using a particular cancer antigen and a corresponding ICI. Target populations include currently untreatable cancer patients or those who receive treatment regimens with high risk of serious side effects. In addition, with the increased use of ICI in clinical practice, questions arise regarding safety and efficacy of administration of conventional vaccines, such as influenza or COVID-19 vaccines, during active ICI treatment. This review discusses the main principles of prophylactic and therapeutic cancer vaccines, the potential impact on combining therapeutic cancer vaccines with ICI, and briefly summarizes the current knowledge of safety and effectiveness of influenza and COVID-19 vaccines in ICI-treated patients.
The immune checkpoint cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is an inhibitory regulator of T-cell mediated responses that has been investigated as target of monoclonal antibodies (mAbs) for cancer immunotherapy. The anti-CTLA-4 mAb ipilimumab represents the first immune checkpoint inhibitor that significantly improved overall survival in patients with unresectable/metastatic melanoma. The subsequent approved indications (often in the first-line setting) for melanoma and other advanced/metastatic solid tumors always require ipilimumab combination with nivolumab, an anti-programmed cell death protein 1 (PD-1) mAb. However, the improved clinical efficacy of the mAb combination is associated with increased immune-related adverse events, which might require treatment discontinuation even in responding patients. This drawback is expected to be overcome by the recent development of anti-CTLA-4 probodies proteolitycally activated in the tumor microenvironment and bispecific molecules targeting both CTLA-4 and PD-1, whose co-expression is characteristic of tumor-infiltrating T cells. These molecules would preferentially stimulate immune responses against the tumor, reducing toxicity toward normal tissues.
Prostate cancer is the second most common cause of cancer‐related death in men in the United States and the fifth worldwide. Most prostate cancer arises as an androgen‐dependent tumor but eventually progresses into castration‐resistance prostate cancer, incurable by the current androgen deprivation therapy and chemotherapy. The development of immunotherapy in cancer treatment has brought an exciting era of antiprostate cancer therapy through antitumor immune responses. Prostate cancer is recognized as a poorly immunogenic tissue with immunological ignorance showing low levels of antigen‐presenting process and cytotoxic T‐cell activation, high levels of immune checkpoint molecules and immunosuppressive cytokines/chemokines, and recruitment of immunosuppressive cells. Immunotherapies for prostate cancer have been developed to activate the innate and adaptive immune responses, such as vaccines and adoptive CAR‐T cells, or to inhibit immunosuppressive molecules, such as immune checkpoint inhibitors or antibodies. The U.S Food and Drug Administration has approved Sipuleucel‐T for the treatment of asymptomatic or minimally symptomatic metastatic castrate‐resistant prostate cancer (mCRPC) and immune checkpoint inhibitor pembrolizumab for the treatment of all solid tumors, including prostate cancer, with impaired mismatch repair genes/microsatellite instability; however, the current clinical outcomes still need to be improved. As various immunosuppressive mechanisms coexist and cross‐interact within the tumor microenvironment, different immunotherapy approaches may have to be combined and selected in a highly personalized way. It is hoped that this rapidly evolving field of immunotherapy will achieve successful treatment for mCRPC and will be applied to a wider range of prostate cancer patients.
Generation of immunity against cancer through vaccination has long been an elusive goal for tumor immunologists. Putative candidates for vaccination targets include oncofetal antigens, viral antigens, neoantigens, and differentiation antigens. The first attempts at cancer vaccination used injections of whole autologous tumor cells. However, these unmodified tumor cells did not engender a robust immune response. Subsequent efforts were focused at enhancing the immunogenicity of whole autologous tumor cell vaccines through genetic modification, often through virally mediated transduction of genes encoding immunostimulatory molecules. Of many immunostimulatory cytokines evaluated in the context of gene‐modified tumor cell vaccines, granulocyte–macrophage colony‐stimulating factor (GM‐CSF) emerged as the most potent in generating protective antitumor immunity. Vaccination using irradiated, GM‐CSF producing tumor cells (GVAX) consistently induced antitumor immunity across several experimental tumor models. The term GVAX can connote GM‐CSF secreting cell vaccines prepared with different vectors as well as vector targets including autologous tumor cells, allogeneic tumor cell lines, and bystander third party tumor cells lines. GVAX has been evaluated against solid tumors, hematologic malignancies, and in the context of hematopoietic stem cell transplantation. GVAX has been extensively studied in clinical trials, both alone and in conjunction with lymphodepleting chemotherapy, immune checkpoint inhibitors, and other vaccines.
Fas (CD95/TNFRSF6), a type-I transmembrane receptor of the tumor necrosis factor receptor (TNFR) superfamily, is a well-known cell death activator. However, it has been also implicated in non-cell death processes including cell survival, differentiation, migration. Whereas the molecular cascade that initiates apoptosis upon Fas engagement with its ligand FasL is particularly well described, the informations concerning the molecular mechanisms underlying the Fas mediated non-apoptotic pathways are sparse.As indicated by the induction of autoimmunity and lymphoproliferation in ALPS patients harboringmutations in either the receptor or its ligand, the Fas/FasL system plays a major role in T cell immune homeostasis and thus, in the control of autoimmunity and cancer. On one side, the Fas mediated death has been described critical for (i) the deletion of autoreactive lymphocytes, and thus in the maintenance of peripheral tolerance; (ii) the control of the number of lymphocytes activated by weak antigens during pathogen infections.On the other side, and beyond cell death induction, some Fas non-death pathways have been described in T cells, among which the role of Fas as co-regulatory receptor for the TCR during its activation. Despite the potential importance of this role in immunotherapeutic strategies, only few and controversial studies related to this involvement were done. Indeed, whereas several studies have described Fas as a TCR co-stimulatory receptor, others defined an inhibition of T cell activation by Fas-TCR concomitant stimulation. In this context, the aim of my PhD project consisted into molecularly dissect the Fas-TCR co-signaling.By using both primary T cells and cell lines bearing a specific transgenic TCR, we could define Fas as a costimulatory receptor. By exploiting biochemical approaches as well as flow cytometry and microscopy we could decipher the Fas-TCR crosstalk both at functional and molecular level. First, we show that Fas-TCR costimulation occurs in both naïve and in memory T cells as well as in both CD4+ and CD8+ T cell subpopulations.Molecularly, we could describe that Fas enhances the TCR signaling at membrane proximal level, since the phosphorylation of the first proteins involved in TCR activation is increased. Furthermore, both membrane-bound and soluble FasL are capable to initiate Fas co-stimulatory signal. Lastly, we could exclude the involvement of FADD and Caspase-8, first actors of Fas signaling, in the co-activation, and even more importantly, the involvement of the death domain of Fas cytoplasmic tail, unveiling the implication of another Fas receptor domain. To describe the molecular mechanisms and the context where Fas-TCR co-stimulation occurs might be of an outstanding importance in the comprehension of Fas physiopathology in T cells and for future studies that might involve its potential for immunotherapeutic strategies.
Macrophages are immune cells that are capable of physically engulfing and clearing whole cells and particles. This process of phagocytosis is modulated by an important interaction between membrane protein CD47, present on all ‘self’ cells, and the macrophage immune-receptor SIRPα. Upon binding to CD47, SIRPα delivers “do not eat me” signals to the macrophage allowing the contact cell or particle to evade engulfment. Cancer cells, which are abnormal human cells, express, and sometimes over-express CD47, which is one mechanism used to escape immune clearance. While there has been success in targeting CD47 on cancer cells in the clinic, indiscriminate binding of anti-CD47 antibodies to CD47 on healthy blood cells is unavoidable, leading to toxic side effects such as anemia. Here, we describe the design and synthesis of short, multivalent, soluble peptide (nano-Self) antagonists engineered to block SIRPα on macrophages. We report potent activity of bivalent and tetravalent nano-Self peptides relative to the monovalent variants in enhancing macrophage engulfment of IgG-opsonized target cells. These multivalent nano-Self peptides associate with macrophages and also suppress tyrosine phosphorylation in macrophages, all consistent with inhibiting the macrophage ‘self’ signaling axis. These peptides potentially serve as novel biomolecular tools for macrophage immunotherapy, replacing anti-CD47 therapies currently being investigated in the clinic.
Immune checkpoint inhibitors (CPIs) have recently become a cornerstone for the treatment of different advanced cancers. These drugs have the ability to reactivate the immune system against tumour cells but can also trigger a myriad of side effects, termed immune-related adverse events (irAEs). Although there are numerous reports of CPI-related endocrinopathies, hypercalcaemia as a suspected irAE is not well documented. The mechanisms of CPI hypercalcaemia are not clearly established. However, in our review, four distinct causes emerged: endocrine disease-related, sarcoid-like granuloma, humoral hypercalcaemia due to parathyroid-related hormone and hyperprogressive disease following CPI initiation. Prompt recognition of hypercalcaemia and the institution of therapy can be lifesaving, affording the opportunity to address the underlying aetiology. In this review we discuss the incidence, diagnosis and management of immune-related hypercalcaemia in oncological patients receiving CPI agents.
Introduction: The incorporation of immune checkpoint inhibitors in the oncologists’ arsenal is a milestone in cancer therapeutics, though not being devoid of toxicities.
Areas covered: The present review provides a comprehensive and up-to-date overview of the immune-related hypophysitis with focus on the elusive biological background, the wide spectrum of the epidemiological profile, the varying clinical aspects, and the diagnostic and therapeutic challenges.
Expert opinion: Historically considered distinctive of anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) monoclonal antibodies (mAbs), the immune-related hypophysitis is increasingly correlated with the anti-programmed cell-death (PD) protein 1 (PD-1)/anti-PD ligand 1 (PD-L1) mAbs. The distinct phenotype of hypophysitis related to anti-PD1/anti-PD-L1 mAbs is highlighted with focus on the immune-related isolated adrenocorticotropic (ACTH) deficiency. The immune-related central diabetes insipidus is discussed as a rare aspect of anti-CTL-A4 mAbs-induced hypophysitis, recently related to anti-PD1/anti-PD-L1 mAbs as well. The present review builds on existing literature concerning immune-related hypophysitis underscoring the pending issues still to be addressed, including (i) pathogenesis; (ii) correlation with preexisting autoimmunity; (iii) predictive value; (iv) utility of high dose glucocorticoids; and (v) establishment of evidence-based diagnostic and therapeutic protocols. Increased awareness and constant vigilance are advocated as cornerstone of a multidisciplinary approach to ensure optimal patients’ care.
We perceive the potential of combined immunotherapy for the synergistic treatment of human papillomavirus (HPV)-associated tumors. So, the tumor inhibiting effects of combination of L. casei TD2a and GM-CSF on the TC-1 growth were evaluated In Vivo using lymphocyte proliferation, lymphocyte cytotoxicity, splenocyte, and tumor cytokine assays. The results showed that tumor inhibition in transplanted mice in the GM-CSF combined with probiotic L. casei group was significantly higher than that observed in the other groups excluding GM-CSF group whose tumor inhibition effect was considerable. The findings also indicated that the combined group could generate tumor-specific cytolytic and splenocyte proliferative responses. The levels of IFN–γ, IL-4, and IL-12 after treating with GM-CSF combined with probiotic L. casei were significantly higher than those of other groups. The intratumoral Tumor Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL) was also significantly increased in the combined group. Tumor analysis further showed that the combined group decreased the accumulation of IL-10 in the tumor microenvironment of treated mice. Furthermore, tumor volume analysis demonstrated that combination group and even GM-CSF suppress tumor growth. Our findings showed that the combination of GM-CSF and probiotic results in improved tumor suppression against HPV-associated tumors and stimulates enhancement of specific antitumor immune responses.
Biosynthesis of extragonadal androgen may contribute to the progression of castration-resistant prostate cancer. We evaluated whether abiraterone acetate, an inhibitor of androgen biosynthesis, prolongs overall survival among patients with metastatic castration-resistant prostate cancer who have received chemotherapy.
We randomly assigned, in a 2:1 ratio, 1195 patients who had previously received docetaxel to receive 5 mg of prednisone twice daily with either 1000 mg of abiraterone acetate (797 patients) or placebo (398 patients). The primary end point was overall survival. The secondary end points included time to prostate-specific antigen (PSA) progression (elevation in the PSA level according to prespecified criteria), progression-free survival according to radiologic findings based on prespecified criteria, and the PSA response rate.
After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo-prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P<0.001), progression-free survival (5.6 months vs. 3.6 months; P<0.001), and PSA response rate (29% vs. 6%, P<0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate-prednisone group than in the placebo-prednisone group.
The inhibition of androgen biosynthesis by abiraterone acetate prolonged overall survival among patients with metastatic castration-resistant prostate cancer who previously received chemotherapy. (Funded by Cougar Biotechnology; COU-AA-301 ClinicalTrials.gov number, NCT00638690.).
To update the 2004 American Society of Clinical Oncology (ASCO) guideline on initial hormonal management of androgen-sensitive, metastatic, recurrent, or progressive prostate cancer (PCa).
The writing committee based its recommendations on an updated systematic literature review. Recommendations were approved by the Expert Panel, the ASCO Health Services Committee, and the ASCO Board of Directors.
Seven randomized controlled trials (four new), one systematic review, one meta-analysis (new), one Markov model, and one delta-method 95% CI procedure for active controlled trials (new) informed the guideline update.
Bilateral orchiectomy or luteinizing hormone-releasing hormone agonists are recommended initial androgen-deprivation treatments (ADTs). Nonsteroidal antiandrogen monotherapy merits discussion as an alternative; steroidal antiandrogen monotherapy should not be offered. Combined androgen blockade should be considered. In metastatic or progressive PCa, immediate versus symptom-onset institution of ADT results in a moderate decrease (17%) in relative risk (RR) for PCa-specific mortality, a moderate increase (15%) in RR for non-PCa-specific mortality, and no overall survival advantage. Therefore, the Panel cannot make a strong recommendation for early ADT initiation. Prostate-specific antigen (PSA) kinetics and other metrics allow identification of populations at high risk for PCa-specific and overall mortality. Further studies must be completed to assess whether patients with adverse prognostic factors gain a survival advantage from immediate ADT. For patients electing to wait until symptoms for ADT, regular monitoring visits are indicated. For patients with recurrence, clinical trials should be considered if available. Currently, data are insufficient to support use of intermittent androgen blockade outside clinical trials
The interaction between the immune system and prostate cancer has been an area of research interest for several decades. The recent U.S. Food and Drug Administration approval of 2 first-in-class proof-of-concept immunotherapies (sipuleucel-T and ipilimumab) has stimulated broader interest in manipulating immunity to fight cancer. In the context of prostate cancer, the immunotherapy strategies that have garnered the most interest are the therapeutic vaccination strategies, exemplified by sipuleucel-T and PROSTVAC-VF, and immune checkpoint blockade of CTLA-4 and PD-1. Improved understanding of the immune responses generated by these strategies and development of predictive biomarkers for patient selection will guide rational combinations of these treatments and provide building blocks for future immunotherapies.
A surge of interest in therapeutic cancer vaccines has arisen in the wake of recent clinical trials suggesting that such vaccines can result in statistically significant and clinically meaningful improvements in overall survival-with substantially limited side effects compared with chemotherapy-in patients with metastatic castration-resistant prostate cancer. One of these trials led to the registration of sipuleucel-T, the first therapeutic vaccine to be approved for cancer patients. In this review we highlight emerging patterns from clinical trials that suggest a need for more-appropriate patient populations (i.e., with lower tumor volume and less-aggressive disease) and endpoints (i.e., overall survival) for studies of immunotherapy alone, as well as biologically plausible explanations for these findings. We also explore the rationale for ongoing and planned studies combining therapeutic vaccines with other modalities. Finally, we attempt to put these findings into a practical clinical context and suggest fertile areas for future study. Although our discussion focuses on prostate cancer, the concepts we address most likely have broad applicability to immunotherapy for other cancers as well.
Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma.
We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival.
Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab-dacarbazine group.
Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.).
To determine safety and feasibility of adjuvant ipilimumab following resection of high-risk melanoma and to identify surrogate markers for benefit.
In this phase II trial, 75 patients with resected stage IIIc/IV melanoma received the CTLA-4 antibody ipilimumab every 6 to 8 weeks for 1 year. Eligible patients received further maintenance treatments. The first 25 patients received 3 mg/kg of ipilimumab, and an additional 50 patients received 10 mg/kg. HLA-A*0201+ patients received multipeptide immunizations in combination with ipilimumab. Leukapheresis was performed prior to and 6 months after initiation of treatment.
Median overall and relapse-free survivals were not reached after a median follow-up of 29.5 months. Significant immune-related adverse events were observed in 28 of 75 patients and were positively associated with longer relapse-free survival. Antigen-specific T cell responses to vaccine were variable, and vaccine combination was not associated with additional benefit. No effects on T regulatory cells were observed. Higher changes in Th-17 inducible frequency were a surrogate marker of freedom from relapse (P = 0.047), and higher baseline C-reactive protein (CRP) levels were associated with freedom from relapse (P = 0.035).
Adjuvant ipilimumab following resection of melanoma at high risk for relapse appeared to be associated with improved outcome compared to historical reports. Significant immune-related adverse events were generally reversible and appeared to be associated with improved relapse-free survival. Although vaccination failed to induce a consistent in vitro measurable response, a higher change in Th-17 inducible cells and higher baseline CRP levels were positively associated with freedom from relapse.
Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment.
We undertook an open-label randomised phase 3 trial in men with metastatic castration-resistant prostate cancer who had received previous hormone therapy, but whose disease had progressed during or after treatment with a docetaxel-containing regimen. Participants were treated with 10 mg oral prednisone daily, and were randomly assigned to receive either 12 mg/m(2) mitoxantrone intravenously over 15-30 min or 25 mg/m(2) cabazitaxel intravenously over 1 h every 3 weeks. The random allocation schedule was computer-generated; patients and treating physicians were not masked to treatment allocation, but the study team was masked to the data analysis. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, NCT00417079.
755 men were allocated to treatment groups (377 mitoxantrone, 378 cabazitaxel) and were included in the intention-to-treat analysis. At the cutoff for the final analysis (Sept 25, 2009), median survival was 15·1 months (95% CI 14·1-16·3) in the cabazitaxel group and 12·7 months (11·6-13·7) in the mitoxantrone group. The hazard ratio for death of men treated with cabazitaxel compared with those taking mitoxantrone was 0·70 (95% CI 0·59-0·83, p<0·0001). Median progression-free survival was 2·8 months (95% CI 2·4-3·0) in the cabazitaxel group and 1·4 months (1·4-1·7) in the mitoxantrone group (HR 0·74, 0·64-0·86, p<0·0001). The most common clinically significant grade 3 or higher adverse events were neutropenia (cabazitaxel, 303 [82%] patients vs mitoxantrone, 215 [58%]) and diarrhoea (23 [6%] vs one [<1%]). 28 (8%) patients in the cabazitaxel group and five (1%) in the mitoxantrone group had febrile neutropenia.
Treatment with cabazitaxel plus prednisone has important clinical antitumour activity, improving overall survival in patients with metastatic castration-resistant prostate cancer whose disease has progressed during or after docetaxel-based therapy.
Sanofi-Aventis.
Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan-Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation.
Sipuleucel-T, an autologous active cellular immunotherapy, has shown evidence of efficacy in reducing the risk of death among men with metastatic castration-resistant prostate cancer.
In this double-blind, placebo-controlled, multicenter phase 3 trial, we randomly assigned 512 patients in a 2:1 ratio to receive either sipuleucel-T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions. The primary end point was overall survival, analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen (PSA) and lactate dehydrogenase.
In the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group (hazard ratio, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P=0.03). This reduction represented a 4.1-month improvement in median survival (25.8 months in the sipuleucel-T group vs. 21.7 months in the placebo group). The 36-month survival probability was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test (hazard ratio, 0.77; 95% CI, 0.61 to 0.97; P=0.02) and after adjustment for use of docetaxel after the study therapy (hazard ratio, 0.78; 95% CI, 0.62 to 0.98; P=0.03). The time to objective disease progression was similar in the two study groups. Immune responses to the immunizing antigen were observed in patients who received sipuleucel-T. Adverse events that were more frequently reported in the sipuleucel-T group than in the placebo group included chills, fever, and headache.
The use of sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer. No effect on the time to disease progression was observed. (Funded by Dendreon; ClinicalTrials.gov number, NCT00065442.)
This phase II study evaluated the safety and activity of ipilimumab, a fully human mAb that blocks cytotoxic T-lymphocyte antigen-4, in patients with advanced melanoma.
Patients with previously treated, unresectable stage III/stage IV melanoma received 10 mg/kg ipilimumab every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. The primary end point was best overall response rate (BORR) using modified World Health Organization (WHO) criteria. We also carried out an exploratory analysis of proposed immune-related response criteria (irRC).
BORR was 5.8% with a disease control rate (DCR) of 27% (N = 155). One- and 2-year survival rates (95% confidence interval) were 47.2% (39.5% to 55.1%) and 32.8% (25.4% to 40.5%), respectively, with a median overall survival of 10.2 months (7.6-16.3). Of 43 patients with disease progression by modified WHO criteria, 12 had disease control by irRC (8% of all treated patients), resulting in a total DCR of 35%. Adverse events (AEs) were largely immune related, occurring mainly in the skin and gastrointestinal tract, with 19% grade 3 and 3.2% grade 4. Immune-related AEs were manageable and generally reversible with corticosteroids.
Ipilimumab demonstrated clinical activity with encouraging long-term survival in a previously treated advanced melanoma population.
Therapeutic prostate-specific antigen (PSA) -targeted poxviral vaccines for prostate cancer have been well tolerated. PROSTVAC-VF treatment was evaluated for safety and for prolongation of progression-free survival (PFS) and overall survival (OS) in a randomized, controlled, and blinded phase II study.
In total, 125 patients were randomly assigned in a multicenter trial of vaccination series. Eligible patients had minimally symptomatic castration-resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3). Vaccinia-based vector was used for priming followed by six planned fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF plus granulocyte-macrophage colony-stimulating factor or to control empty vectors plus saline injections.
Eighty-two patients received PROSTVAC-VF and 40 received control vectors. Patient characteristics were similar in both groups. The primary end point was PFS, which was similar in the two groups (P = .6). However, at 3 years post study, PROSTVAC-VF patients had a better OS with 25 (30%) of 82 alive versus 7 (17%) of 40 controls, longer median survival by 8.5 months (25.1 v 16.6 months for controls), an estimated hazard ratio of 0.56 (95% CI, 0.37 to 0.85), and stratified log-rank P = .0061.
PROSTVAC-VF immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS in men with mCRPC. These provocative data provide preliminary evidence of clinically meaningful benefit but need to be confirmed in a larger phase III study.
Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) therapies represent a novel approach to cancer treatment via disruption of immune tolerance to antigens located on tumor cells. Disruption of immune tolerance, however, may occur at a cost. A host of immune related adverse events (IRAEs) are associated with anti-CTLA-4 therapy. Autoimmune hypophysitis has been reported in up to 17% of patients with melanoma and renal cell carcinoma treated with this therapy. Familiarity with the spectrum of IRAEs connected to these therapies is paramount for endocrinologists, oncologists and those involved in the care of these subjects. We review here key aspects of diagnosis and treatment of anti-CTLA-4 antibody therapy resultant IRAEs. We describe the first two cases of hypopituitarism in prostate cancer subjects undergoing experimental therapy with ipilimumab. The clinical evidence strongly suggests that the prostate cancer subjects developed autoimmune hypophysitis as a consequence of anti-CTLA-4 treatment. High dose glucocorticoid treatment resulted in markedly improved symptoms, and resolution of focal symptoms and diabetes insipidus. One subject recovered pituitary-thyroid axis function after 9 months; however, both continue to require GC replacement. These cases highlight the importance of early screening and treatment for hypopituitarism in all subjects undergoing treatment with anti-CTLA-4 therapy to prevent a potentially fatal outcome from secondary adrenal insufficiency, a readily treatable disease. We recommend mandatory long term follow-up to monitor the development of other hormonal deficits.
To compare the ability of different cytokines and other molecules to enhance the immunogenicity of tumor cells, we generated 10 retroviruses encoding potential immunomodulators and studied the vaccination properties of murine tumor cells transduced by the viruses. Using a B16 melanoma model, in which irradiated tumor cells alone do not stimulate significant anti-tumor immunity, we found that irradiated tumor cells expressing murine granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated potent, long-lasting, and specific anti-tumor immunity, requiring both CD4+ and CD8+ cells. Irradiated cells expressing interleukins 4 and 6 also stimulated detectable, but weaker, activity. In contrast to the B16 system, we found that in a number of other tumor models, the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone. Nevertheless, manipulation of the vaccine or challenge doses made it possible to demonstrate the activity of murine GM-CSF in those systems as well. Overall, our results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines.
We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte/macrophage colony-stimulating factor (GM-CSF)-expressing tumor cell vaccine, on rejection of the highly tumorigenic, poorly immunogenic murine melanoma B16-BL6. Recently established tumors could be eradicated in 80% (68/85) of the cases using combination treatment, whereas each treatment by itself showed little or no effect. Tumor rejection was dependent on CD8(+) and NK1.1(+) cells but occurred irrespective of the presence of CD4(+) T cells. Mice surviving a primary challenge rejected a secondary challenge with B16-BL6 or the parental B16-F0 line. The same treatment regimen was found to be therapeutically effective against outgrowth of preestablished B16-F10 lung metastases, inducing long-term survival. Of all mice surviving B16-BL6 or B16-F10 tumors after combination treatment, 56% (38/68) developed depigmentation, starting at the site of vaccination or challenge and in most cases progressing to distant locations. Depigmentation was found to occur in CD4-depleted mice, strongly suggesting that the effect was mediated by CTLs. This study shows that CTLA-4 blockade provides a powerful tool to enhance T cell activation and memory against a poorly immunogenic spontaneous murine tumor and that this may involve recruitment of autoreactive T cells.
Mitoxantrone-based chemotherapy palliates pain without extending survival in men with progressive androgen-independent prostate cancer. We compared docetaxel plus estramustine with mitoxantrone plus prednisone in men with metastatic, hormone-independent prostate cancer.
We randomly assigned 770 men to one of two treatments, each given in 21-day cycles: 280 mg of estramustine three times daily on days 1 through 5, 60 mg of docetaxel per square meter of body-surface area on day 2, and 60 mg of dexamethasone in three divided doses before docetaxel, or 12 mg of mitoxantrone per square meter on day 1 plus 5 mg of prednisone twice daily. The primary end point was overall survival; secondary end points were progression-free survival, objective response rates, and post-treatment declines of at least 50 percent in serum prostate-specific antigen (PSA) levels.
Of 674 eligible patients, 338 were assigned to receive docetaxel and estramustine and 336 to receive mitoxantrone and prednisone. In an intention-to-treat analysis, the median overall survival was longer in the group given docetaxel and estramustine than in the group given mitoxantrone and prednisone (17.5 months vs. 15.6 months, P=0.02 by the log-rank test), and the corresponding hazard ratio for death was 0.80 (95 percent confidence interval, 0.67 to 0.97). The median time to progression was 6.3 months in the group given docetaxel and estramustine and 3.2 months in the group given mitoxantrone and prednisone (P<0.001 by the log-rank test). PSA declines of at least 50 percent occurred in 50 percent and 27 percent of patients, respectively (P<0.001), and objective tumor responses were observed in 17 percent and 11 percent of patients with bidimensionally measurable disease, respectively (P=0.30). Grade 3 or 4 neutropenic fevers (P=0.01), nausea and vomiting (P<0.001), and cardiovascular events (P=0.001) were more common among patients receiving docetaxel and estramustine than among those receiving mitoxantrone and prednisone. Pain relief was similar in both groups.
The improvement in median survival of nearly two months with docetaxel and estramustine, as compared with mitoxantrone and prednisone, provides support for this approach in men with metastatic, androgen-independent prostate cancer.
Mitoxantrone plus prednisone reduces pain and improves the quality of life in men with advanced, hormone-refractory prostate cancer, but it does not improve survival. We compared such treatment with docetaxel plus prednisone in men with this disease.
From March 2000 through June 2002, 1006 men with metastatic hormone-refractory prostate cancer received 5 mg of prednisone twice daily and were randomly assigned to receive 12 mg of mitoxantrone per square meter of body-surface area every three weeks, 75 mg of docetaxel per square meter every three weeks, or 30 mg of docetaxel per square meter weekly for five of every six weeks. The primary end point was overall survival. Secondary end points were pain, prostate-specific antigen (PSA) levels, and the quality of life. All statistical comparisons were against mitoxantrone.
As compared with the men in the mitoxantrone group, men in the group given docetaxel every three weeks had a hazard ratio for death of 0.76 (95 percent confidence interval, 0.62 to 0.94; P=0.009 by the stratified log-rank test) and those given weekly docetaxel had a hazard ratio for death of 0.91 (95 percent confidence interval, 0.75 to 1.11; P=0.36). The median survival was 16.5 months in the mitoxantrone group, 18.9 months in the group given docetaxel every 3 weeks, and 17.4 months in the group given weekly docetaxel. Among these three groups, 32 percent, 45 percent, and 48 percent of men, respectively, had at least a 50 percent decrease in the serum PSA level (P<0.001 for both comparisons with mitoxantrone); 22 percent, 35 percent (P=0.01), and 31 percent (P=0.08) had predefined reductions in pain; and 13 percent, 22 percent (P=0.009), and 23 percent (P=0.005) had improvements in the quality of life. Adverse events were also more common in the groups that received docetaxel.
When given with prednisone, treatment with docetaxel every three weeks led to superior survival and improved rates of response in terms of pain, serum PSA level, and quality of life, as compared with mitoxantrone plus prednisone.
Evading antitumor immune responses is an important aspect of the pathogenesis of head and neck squamous cell carcinoma (HNSCC). Invariant CD1d-restricted natural killer T (iNKT) cells play an allegedly pivotal role in such responses via transactivation of immune effector cells. It has been reported that iNKT cells are reduced in peripheral blood of cancer patients compared with healthy controls. Here, we investigated whether the extent of this deficiency affected disease outcome in HNSCC patients.
In a prospective study, circulating iNKT cell numbers were evaluated in 47 patients before radiotherapy. Patients were stratified in three groups based on iNKT cell levels, and clinical data were obtained during a median follow-up period of 31 months.
A small, compared with an intermediate or large, circulating iNKT cell fraction was significantly associated with decreased 3-year overall survival rate (39% v 75% and 92%, respectively), disease-specific survival rate (43% v 87% and 92%, respectively), and locoregional control rate (31% v 74% and 92%, respectively) in HNSCC patients. Cox regression revealed that the iNKT cell level, as well as clinical T stage, was an independent prognostic parameter even after correction for the confounding effect of age.
A severe circulating iNKT cell deficiency was related to poor clinical outcome in HNSCC patients, suggesting their critical contribution to antitumor immune responses. Furthermore, screening for iNKT cell levels may be useful for determining which patients can benefit from immunotherapeutic adjuvant therapies aimed at reconstitution of the circulating iNKT cell pool.
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) functions as a negative regulator of endogenous and vaccine-induced antitumor immunity. The administration of fully human anti-CTLA-4 blocking monoclonal antibodies to advanced-cancer patients increases immune-mediated tumor destruction in some subjects. Nonetheless, patients that respond also frequently manifest serious inflammatory pathologies, raising the possibility that the therapeutic and toxic effects of CTLA-4 blockade might be linked. Here we show that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients. The application of this sequential immunotherapy to advanced ovarian carcinoma patients also revealed that tumor destruction and severe inflammatory pathology could be dissociated, although further refinements are required to increase clinical responses and to minimize toxicity in this population. The extent of therapy-induced tumor necrosis was linearly related to the natural logarithm of the ratio of intratumoral CD8⁺ effector T cells to FoxP3⁺ regulatory T cells (Tregs) in posttreatment biopsies. Together, these findings help clarify the immunologic and clinical effects of CTLA-4 antibody blockade in previously vaccinated patients and raise the possibility that selective targeting of antitumor Tregs may constitute a complementary strategy for combination therapy.
• CTLA-4
• regulatory T cells (Tregs)
• vaccine
• GM-CSF
To update eligibility and outcome measures in trials that evaluate systemic treatment for patients with progressive prostate cancer and castrate levels of testosterone.
A committee of investigators experienced in conducting trials for prostate cancer defined new consensus criteria by reviewing previous criteria, Response Evaluation Criteria in Solid Tumors (RECIST), and emerging trial data.
The Prostate Cancer Clinical Trials Working Group (PCWG2) recommends a two-objective paradigm: (1) controlling, relieving, or eliminating disease manifestations that are present when treatment is initiated and (2) preventing or delaying disease manifestations expected to occur. Prostate cancers progressing despite castrate levels of testosterone are considered castration resistant and not hormone refractory. Eligibility is defined using standard disease assessments to authenticate disease progression, prior treatment, distinct clinical subtypes, and predictive models. Outcomes are reported independently for prostate-specific antigen (PSA), imaging, and clinical measures, avoiding grouped categorizations such as complete or partial response. In most trials, early changes in PSA and/or pain are not acted on without other evidence of disease progression, and treatment should be continued for at least 12 weeks to ensure adequate drug exposure. Bone scans are reported as "new lesions" or "no new lesions," changes in soft-tissue disease assessed by RECIST, and pain using validated scales. Defining eligibility for prevent/delay end points requires attention to estimated event frequency and/or random assignment to a control group.
PCWG2 recommends increasing emphasis on time-to-event end points (ie, failure to progress) as decision aids in proceeding from phase II to phase III trials. Recommendations will evolve as data are generated on the utility of intermediate end points to predict clinical benefit.
This open-label, multicenter, dose-escalation study evaluated multiple dose levels of immunotherapy in patients with metastatic hormone-refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX platform, consisted of 2 allogeneic prostate-carcinoma cell lines modified to secrete granulocyte-macrophage-colony-stimulating factor (GM-CSF).
Dose levels ranged from 100 x 10(6) cells q28d x 6 to 500 x 10(6) cells prime/300 x 10(6) cells boost q14d x 11. Endpoints included safety, immunogenicity, overall survival, radiologic response, prostate-specific antigen (PSA) kinetics, and serum GM-CSF pharmacokinetics.
Eighty men, median age 69 years (range, 49-90 years), were treated. The most common adverse effect was injection-site erythema. Overall, the immunotherapy was well tolerated. A maximal tolerated dose was not established. The median survival time was 35.0 months in the high-dose group, 20.0 months in the mid-dose, group, and 23.1 months in the low-dose group. PSA stabilization occurred in 15 (19%) patients, and a >50% decline in PSA was seen in 1 patient. The proportion of patients who generated an antibody response to 1 or both cell lines increased with dose and included 10 of 23 (43%) in the low-dose group, 13 of 18 (72%) in the mid-dose group, and 16 of 18 (89%) in the high-dose group (P = .002; Cochran-Armitage trend test).
This immunotherapy was well tolerated. Immunogenicity and overall survival varied by dose. Two phase 3 trials in patients with metastatic HRPC are underway.
Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. A total of 1,596,670 new cancer cases and 571,950 deaths from cancer are projected to occur in the United States in 2011. Overall cancer incidence rates were stable in men in the most recent time period after decreasing by 1.9% per year from 2001 to 2005; in women, incidence rates have been declining by 0.6% annually since 1998. Overall cancer death rates decreased in all racial/ethnic groups in both men and women from 1998 through 2007, with the exception of American Indian/Alaska Native women, in whom rates were stable. African American and Hispanic men showed the largest annual decreases in cancer death rates during this time period (2.6% and 2.5%, respectively). Lung cancer death rates showed a significant decline in women after continuously increasing since the 1930s. The reduction in the overall cancer death rates since 1990 in men and 1991 in women translates to the avoidance of about 898,000 deaths from cancer. However, this progress has not benefitted all segments of the population equally; cancer death rates for individuals with the least education are more than twice those of the most educated. The elimination of educational and racial disparities could potentially have avoided about 37% (60,370) of the premature cancer deaths among individuals aged 25 to 64 years in 2007 alone. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population with an emphasis on those groups in the lowest socioeconomic bracket.
Prostate specific membrane antigen (PSMA) is a suggested target for antibody-based therapy of prostate cancer potentially involved in the regulation of cell migration. This study was undertaken, to gain more insight on the role of PSMA in early prostate cancer and its distribution in various normal tissues.
A total of 1,700 different prostate cancers treated by radical prostatectomy and 612 samples from 76 different normal tissue types were successfully analyzed by immunohistochemistry (IHC) in a tissue microarray (TMA) format. PSMA immunostaining in cancers was also compared with clinical follow-up, preexisting HER2 expression and Ki67 labeling index data.
PSMA staining was only found in prostate epithelium and expression was higher in cancer cells than in benign tissue. PSMA staining was found in 94.1% of cancers and was significantly associated with tumor stage, high Gleason grade, preoperative PSA, and HER2 expression (P < 0.0001 each). Tumors with strong PSMA expression had a higher risk of biochemical recurrence than cancers with only weak PSMA staining intensity (P = 0.0483). There was no significant association between PSMA expression and Ki67 labeling index (P = 0.442).
Based on the high frequency of PSMA overexpression in all stages and grades of prostate cancer and the high prevalence of PSMA overexpression, it can be speculated that increased PSMA expression may be related with prostate cancer development rather than progression. The known function of PSMA activating cell migration would be in line with the suggested role in cancer progression and the missing association between PSMA overexpression and tumor cell proliferation.
Advances in basic immunology have led to an improved understanding of the interactions between the immune system and tumours, generating renewed interest in approaches that aim to treat cancer immunologically. As clinical and preclinical studies of tumour immunotherapy illustrate several immunological principles, a review of these data is broadly instructive and is particularly timely now that several agents are beginning to show evidence of efficacy. This is especially relevant in the case of prostate cancer, as recent approval of sipuleucel-T by the US Food and Drug Administration marks the first antigen-specific immunotherapy approved for cancer treatment. Although this Review focuses on immunotherapy for prostate cancer, the principles discussed are applicable to many tumour types, and the approaches discussed are highlighted in that context.
Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data regarding cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,529,560 new cancer cases and 569,490 deaths from cancer are projected to occur in the United States in 2010. Overall cancer incidence rates decreased in the most recent time period in both men (1.3% per year from 2000 to 2006) and women (0.5% per year from 1998 to 2006), largely due to decreases in the 3 major cancer sites in men (lung, prostate, and colon and rectum [colorectum]) and 2 major cancer sites in women (breast and colorectum). This decrease occurred in all racial/ethnic groups in both men and women with the exception of American Indian/Alaska Native women, in whom rates were stable. Among men, death rates for all races combined decreased by 21.0% between 1990 and 2006, with decreases in lung, prostate, and colorectal cancer rates accounting for nearly 80% of the total decrease. Among women, overall cancer death rates between 1991 and 2006 decreased by 12.3%, with decreases in breast and colorectal cancer rates accounting for 60% of the total decrease. The reduction in the overall cancer death rates translates to the avoidance of approximately 767,000 deaths from cancer over the 16-year period. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, geographic area, and calendar year. Although progress has been made in reducing incidence and mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons younger than 85 years. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population and by supporting new discoveries in cancer prevention, early detection, and treatment.
An improvement in overall survival among patients with metastatic melanoma has been an elusive goal. In this phase 3 study, ipilimumab--which blocks cytotoxic T-lymphocyte-associated antigen 4 to potentiate an antitumor T-cell response--administered with or without a glycoprotein 100 (gp100) peptide vaccine was compared with gp100 alone in patients with previously treated metastatic melanoma.
A total of 676 HLA-A*0201-positive patients with unresectable stage III or IV melanoma, whose disease had progressed while they were receiving therapy for metastatic disease, were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab plus gp100 (403 patients), ipilimumab alone (137), or gp100 alone (136). Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with or without gp100 every 3 weeks for up to four treatments (induction). Eligible patients could receive reinduction therapy. The primary end point was overall survival.
The median overall survival was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (hazard ratio for death, 0.68; P<0.001). The median overall survival with ipilimumab alone was 10.1 months (hazard ratio for death in the comparison with gp100 alone, 0.66; P=0.003). No difference in overall survival was detected between the ipilimumab groups (hazard ratio with ipilimumab plus gp100, 1.04; P=0.76). Grade 3 or 4 immune-related adverse events occurred in 10 to 15% of patients treated with ipilimumab and in 3% treated with gp100 alone. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune-related adverse events.
Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma. Adverse events can be severe, long-lasting, or both, but most are reversible with appropriate treatment. (Funded by Medarex and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00094653.)
A critical factor in clinical development of cancer immunotherapies is the identification of tumor-associated antigens that may be related to immunotherapy potency. In this study, protein microarrays containing >8,000 human proteins were screened with serum from prostate cancer patients (N = 13) before and after treatment with a granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting whole cell immunotherapy. Thirty-three proteins were identified that displayed significantly elevated (P <or= 0.05) signals in post-treatment samples, including three proteins that have previously been associated with prostate carcinogenesis, galectin-8, T-cell alternative reading frame protein (TARP) and TNF-receptor-associated protein 1 (TRAP1). Expanded analysis of antibody induction in metastatic, castration-resistant prostate cancer (mCRPC) patients (N = 92) from two phase 1/2 trials of prostate cancer immunotherapy, G-9803 and G-0010, indicated a significant (P = 0.03) association of TARP antibody induction and median survival time (MST). Antibody induction to TARP was also significantly correlated (P = 0.036) with an increase in prostate-specific antigen doubling time (PSADT) in patients with a biochemical (PSA) recurrence following prostatectomy or radiation therapy (N = 19) from in a previous phase 1/2 trial of prostate cancer immunotherapy, G-9802. RNA and protein encoding TARP and TRAP1 was up-regulated in prostate cancer tissue compared to matched normal controls. These preliminary findings suggest that antibody induction to TARP may represent a possible biomarker for treatment response to GM-CSF secreting cellular immunotherapy in prostate cancer patients and demonstrates the utility of using protein microarrays for the high-throughput screening of patient-derived antibody responses.
Considerable progress has been made in prostate cancer immunotherapy over the last year, and two agents have completed phase III testing. This review will discuss the most promising immune-directed strategies in development for prostate cancer, outlining interventions that mitigate tumor-induced tolerance and highlighting several combination immunotherapy approaches.
A pivotal phase III study using Sipuleucel-T, an autologous prostatic acid phosphatase (PAP)-loaded dendritic cell immunotherapy, in men with metastatic castration-resistant prostate cancer (CRPC) demonstrated a survival advantage over placebo. By contrast, two phase III studies of GVAX, an allogeneic tumor cell vaccine, in a similar patient population failed to show a survival benefit of GVAX or GVAX/docetaxel over standard docetaxel/prednisone. Other strategies currently in clinical development include the ProstVac poxviral vaccine, a PAP-encoding DNA vaccine, and immune checkpoint inhibitory approaches.
Although Sipuleucel-T may receive FDA approval for patients with metastatic CRPC, challenges remain in identifying immunotherapy strategies that overcome immune tolerance, especially when disease burden is substantial. An emerging paradigm focuses on using immunotherapy together with checkpoint antagonists or in combination with conventional therapies in patients with early-stage disease. Such approaches are likely to yield optimal results, but must carefully be explored in well designed phase II studies before moving forward.
Ipilimumab is a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 and has shown promising activity in advanced melanoma. We aimed to ascertain the antitumour efficacy of ipilimumab in patients with advanced melanoma.
We undertook a randomised, double-blind, phase 2 trial in 66 centres from 12 countries. 217 patients with previously treated stage III (unresectable) or stage IV melanoma were randomly assigned a fixed dose of ipilimumab of either 10 mg/kg (n=73), 3 mg/kg (n=72), or 0.3 mg/kg (n=72) every 3 weeks for four cycles (induction) followed by maintenance therapy every 3 months. Randomisation was done with a permuted block procedure, stratified on the basis of type of previous treatment. The primary endpoint was best overall response rate (the proportion of patients with a complete or partial response, according to modified WHO criteria). Efficacy analyses were done by intention to treat, whereas safety analyses included patients who received at least one dose of ipilimumab. This study is registered with ClinicalTrials.gov, number NCT00289640.
The best overall response rate was 11.1% (95% CI 4.9-20.7) for 10 mg/kg, 4.2% (0.9-11.7) for 3 mg/kg, and 0% (0.0-4.9) for 0.3 mg/kg (p=0.0015; trend test). Immune-related adverse events of any grade arose in 50 of 71, 46 of 71, and 19 of 72 patients at doses of 10 mg/kg, 3 mg/kg, and 0.3 mg/kg, respectively; the most common grade 3-4 adverse events were gastrointestinal immune-related events (11 in the 10 mg/kg group, two in the 3 mg/kg group, none in the 0.3 mg/kg group) and diarrhoea (ten in the 10 mg/kg group, one in the 3 mg/kg group, none in the 0.3 mg/kg group).
Ipilimumab elicited a dose-dependent effect on efficacy and safety measures in pretreated patients with advanced melanoma, lending support to further studies at a dose of 10 mg/kg.
Bristol-Myers Squibb.
One reason for the poor immunogenicity of many tumors may be that they cannot provide signals for CD28-mediated costimulation necessary to fully activate T cells. It has recently become apparent that CTLA-4, a second counterreceptor for the B7 family of costimulatory molecules, is a negative regulator of T cell activation. Here, in vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors. Furthermore, this rejection resulted in immunity to a secondary exposure to tumor cells. These results suggest that blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune responses against tumor cells.
Prostate cancer is the second-leading cause of cancer-related death among men and the seventh most common cause of death in the United States overall. Most prostate cancers are androgen-dependent, meaning that they respond to androgen-ablation therapy. However, these tumors eventually become androgen-independent and grow despite androgen ablation. When prostate cancer is localized in the prostate, the treatment of choice is prostatectomy or irradiation. However, when the tumor relapses or is already metastatic at diagnosis, therapy is problematic. Androgen ablation has been the main option for unconfined disease for more than 50 years, since Clarence V. Hodges and Charles B. Huggins . . .
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is an immunoregulatory molecule expressed by activated T cells and resting CD4CD25 T cells. In patients with advanced melanoma, our group reported that administration of anti-CTLA-4 antibody mediated objective cancer regression in 13% of patients. This study also established that the blockade of CTLA-4 was associated with grade III/IV autoimmune manifestations that included dermatitis, enterocolitis, hepatitis, uveitis, and a single case of hypophysitis. Since this initial report, 7 additional patients with anti-CTLA-4 antibody-induced autoimmune hypophysitis have been accumulated. The characteristics, clinical course, laboratory values, radiographic findings, and treatment of these 8 patients are the focus of this report.
To determine the toxicity, immunologic, and clinical activity of immunotherapy with irradiated, allogeneic, prostate cancer cells expressing granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with recurrent prostate cancer.
A single-institution phase I/II trial was done in hormone therapy-naïve patients with prostate-specific antigen (PSA) relapse following radical prostatectomy and absence of radiologic metastases. Treatments were administered weekly via intradermal injections of 1.2 x 10(8) GM-CSF gene-transduced, irradiated, cancer cells (6 x 10(7) LNCaP cells and 6 x 10(7) PC-3 cells) for 8 weeks.
Twenty-one patients were enrolled and treated. Toxicities included local injection-site reactions, pruritus, and flu-like symptoms. One patient had a partial PSA response of 7-month duration. At 20 weeks post first treatment, 16 of 21 (76%) patients showed a statistically significant decrease in PSA velocity (slope) compared with prevaccination (P < 0.001). Injection site biopsies showed intradermal infiltrates consisting of CD1a+ dendritic cells and CD68+ macrophages, similar to previous clinical trials using autologous GM-CSF-transduced cancer cells. Posttreatment, patients developed new oligoclonal antibodies reactive against at least five identified antigens present in LNCaP or PC-3 cells. A high-titer antibody response against a 250-kDa antigen expressed on normal prostate epithelial cells was induced in a patient with partial PSA remission; titers of this antibody decreased when treatment ended, and subsequent PSA relapse occurred.
This non-patient-specific prostate cancer immunotherapy has a favorable safety profile and is immunologically active. Continued clinical investigation at higher doses and with longer boosting schedules is warranted.
New approaches to therapeutics of advanced prostate cancer are urgently needed. GVAX (granulocyte-macrophage colony-stimulating factor [GM-CSF] gene transduced irradiated prostate cancer vaccine cells) offers the possibility that "host versus prostate cancer" immune responses can be generated in prostate cancer patients. Critical components involve the dendritic cell loading of candidate prostate cancer lymph node metastasis and candidate bone metastasis antigens derived from irradiated prostate cancer whole cells. GM-CSF acts at the vaccination site to enhance activation dendritic cells and antigen presentation to both the B-cell and T-cell arms of the immune system. GVAX preclinically-in both rat and transgenic prostate cancer models-has antitumor activity which has informed early clinical trial designs. Clinical investigations reviewed in this report suggest that vaccination is safe and immune tolerance can be broken against prostate cancer. Multi-institutional phase III investigation is currently underway to evaluate the impact of allogeneic prostate GVAX cellular immunotherapy on time to progression and overall survival in hormone refractory prostate cancer.
Blockade of the T-cell inhibitory receptor CTL-associated antigen-4 (CTLA-4) augments and prolongs T-cell responses and is a strategy to elicit antitumor immunity. The objectives of this pilot study were to establish the pharmacokinetic and safety profile for a single dose of 3 mg/kg of the anti-CTLA-4 antibody Ipilimumab (MDX-010, BMS-734016) and to assess if this therapy resulted in prostate-specific antigen (PSA) modulation and the development of polyclonal T-cell activation and/or clinical autoimmunity in patients with hormone-refractory prostate cancer treated with Ipilimumab.
Patients with metastatic hormone-refractory prostate cancer received a single 3 mg/kg i.v. dose of Ipilimumab. Serologic measures of autoimmunity were obtained, and T-cell activation was evaluated by flow cytometry. Pharmacokinetic sampling of plasma for MDX-CTLA-4, PSA measurement, and diagnostic imaging were also undertaken.
Fourteen patients were treated: 12 patients received a single dose of Ipilimumab, and 2 patients were re-treated with a second dose upon PSA progression. Two patients showed PSA declines of > or =50%. Treatment was well tolerated with clinical autoimmunity limited to one patient who developed grade 3 rash/pruritus requiring systemic corticosteroids. The mean +/- SD Ipilimumab terminal elimination half-life was 12.5 +/- 5.3 days.
A single dose of 3 mg/kg Ipilimumab, an anti-CTLA-4 antibody, given to patients with prostate cancer is safe and does not result in significant clinical autoimmunity. PSA-modulating effects observed warrant further investigation.
This trial evaluated the safety, clinical activity, and immunogenicity of an allogeneic cellular immunotherapy in 55 chemotherapy-naïve patients with hormone-refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX platform, is a combination of two prostate carcinoma cell lines modified with the granulocyte macrophage colony-stimulating factor (GM-CSF) gene.
HRPC patients with radiologic metastases (n = 34) or rising prostate-specific antigen (PSA) only (n = 21) received a prime dose of 500 million cells and 12 boost doses of either 100 million cells (low dose) or 300 million cells (high dose) biweekly for 6 months. End points were changes in PSA, time to progression, and survival.
Median survival was 26.2 months (95% confidence interval, 17, 36) in the radiologic group: 34.9 months (8, 57) after treatment with the high dose (n = 10) of immunotherapy and 24.0 months (11, 35) with the low dose (n = 24). The median time to bone scan progression in the radiologic group was 5.0 months (2.6, 11.6) with the high dose and 2.8 months (2.8, 5.7) with the low dose. In the rising-PSA group (n = 21) receiving the low dose, the median time to bone scan progression was 5.9 months (5.6, not reached), and median survival was 37.5 months (29, 56). No dose-limiting or autoimmune toxicities were seen; the most common adverse events were injection site reaction and fatigue.
These results suggest that this GM-CSF-secreting, allogeneic cellular immunotherapy is well tolerated and may have clinical activity in patients with metastatic HRPC. Phase 3 trials to confirm these results are under way.
Learning Objectives
After completing this course, the reader will be able to: Describe the completed and ongoing clinical trials of ipilimumab in patients with advanced melanoma.Discuss the nature of immune-mediated adverse events, which are often associated with ipilimumab treatment.Describe several cases illustrating the kinetics of ipilimumab-mediated antitumor responses and the relationship to immune-mediated adverse events.
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