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Murine monoclonal antibodies of the immunoglobulin G2a isotype interact with human effector cells to mediate antibody-dependent cellular cytotoxicity (ADCC) directed against malignant cells which express antigens recognized by these antibodies. gamma-Interferon enhances these effects in vitro. In a Phase I trial of murine monoclonal antibody CO17-1...
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Context 1
... tumor pO2 levels were prospectively de termined in II lesions from 10 patients in this study. Mean pO2 in each tumor ranged from 1 to 34 mm Hg (Table 3) Table 2 Relationship of 17-IA antigen expression to "'¡-17-IA imaging and therapeutic antibody delivery * The same lesions were biopsied posttherapy and evaluated for antigen expression using CO 17-IA and therapeutic antibody delivery using a conjugated antimouse antibody only. Results were interpreted as described above and in the test. ...
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... it did not image with labeled 17-IA and no antibody was detected in the mass at the completion of therapy. The mean pO2 of the lesion was 2-3 mm Hg (Table 3), and hypoxia appeared more important than antigen expression in determining the accessibility of the malignant cells to the anti body. ...
Citations
... There were no objective responses in either study. 164,165 Ragnhammar et al. 166 administered edrecolomab with granulocytemacrophage colony-stimulating factor to 20 patients and reported two CRs, a 10% response rate. Edrecolomab was administered with IL-2 to 32 patients and produced one PR. ...
Monoclonal antibodies used in the treatment of cancer are discussed.
Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. In addition to having direct cellular effects, antibodies can carry substances, such as radioactive isotopes, toxins, and antineoplastic agents, to the targeted cells. Five monoclonal antibodies—rituximab, trastuzumab, gemtuzumab ozogamicin, alemtuzumab, and ibritumomab tiuxetan—are available for clinical use. Rituximab is active against indolent lymphomas, providing a valuable alternative for patients with relapsed or refractory disease. Rituximab plus cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) increased survival over CHOP alone in patients with high-grade lymphomas. Trastuzumab has significant activity against HER-2-positive breast cancer, especially in combination with paclitaxel or an anthracycline and cyclophosphamide. Gemtuzumab ozogamicin is an active second-line therapy in older patients with acute myelogenous leukemia, but its role in combination regimens is unclear. Alemtuzumab is a valuable option for salvage therapy of patients with chronic lymphocytic leukemia. Ibritumomab tiuxetan delivers radioactive isotopes to tumor cells and is active against indolent lymphomas in patients who have relapsed after chemotherapy or rituximab therapy. The most common adverse effects of monoclonal antibodies are myelosuppression, infusion-related reactions, and hypersensitivity reactions. Rituximab may cause tumor lysis syndrome, arrhythmias, and pulmonary dysfunction. Alemtuzumab causes immunosuppression, increasing the risk of infection. Gemtuzumab ozogamicin may cause hepatotoxicity, and trastuzumab may cause significant pulmonary or cardiac toxicity. Investigational monoclonal antibodies include edrecolomab and tositumomab.
Monoclonal antibodies have a significant role in the management of patients with advanced refractory or relapsed lymphomas and leukemias.
... First, in support of this concept, we found that binding of rituximab was increased on MM plasma cells after culture with IFN-␥. Second, the combination of IFN-␥ with CD20-directed serotherapy is appealing because IFN-␥ activates NK cells and monocytes, augments circulating NK cells, and stimulates Fc receptor expression on these cells (58)(59)(60)(61)(62). Increased effector cells may enhance the activity of rituximab, because the response to rituximab correlated with the number of circulating NK cells in NHL patients (63). ...
... In single-agent phase I studies, IFN-␥ has also exhibited some activity in MM patients (69). Finally, the administration of IFN-␥ in combination with serotherapy in patients appears feasible, based on the work of Weiner and colleagues (59). These investigations, coupled with the demonstration in this study that IFN-␥ induces CD20 on MM plasma cells and MM B cells and augments rituximab binding to MM plasma cells, provide the rationale for the use of IFN-␥ pretreatment and CD20-directed serotherapies for MM. ...
Clonotypic B cells circulating in patients with multiple myeloma (MM) express CD20, and it has been suggested that these cells may be clonogenic. Furthermore, 20% of patients with MM express CD20 on their bone marrow plasma cells (BMPCs). Therefore, the authors began a phase II clinical study to determine the activity of the anti-CD20 monoclonal antibody rituximab in MM patients. Nineteen previously treated MM patients received 375 mg/m2 rituximab per week for 4 weeks. Three months after initiation of treatment, patients were assessed for response and received a second course of therapy if their disease was stable (SD) or they achieved a partial response (PR). Six of 19 (32%) patients had either a PR (n = 1) or SD (n = 5), with a median time to treatment failure of 5.5 months (mean, 10.3 months; range, 3-27+ months). All six patients who had a PR or SD had CD20+ BMPC. Overall, rituximab therapy was well tolerated. Because most patients with MM poorly express CD20 on their BMPCs, the authors evaluated agents for their ability to induce CD20 expression and thereby facilitate rituximab binding on MM cells. These studies show that interferon-gamma (IFN-y) induced CD20 expression on MM BMPCs, MM B cells, and healthy donor BMPCs. In contrast, CD20 expression on chronic lymphocytic leukemia, follicular non-Hodgkin's lymphoma, healthy donor B cells, and progenitor cells was unaffected by IFN-y. Rituximab binding to the BMPCs of MM patients was also increased after culture with pharmacologically attainable levels of IFN-gamma (1-100 U/mL). In conclusion, these studies suggest that MM patients with CD20+ BMPCs may benefit from rituximab therapy. Furthermore, IFN-gamma induces CD20 expression on MM BMPCs and B cells and facilitates rituximab binding to MM BMPCs, providing the rationale for clinical trials to examine its use with CD20-directed serotherapies in MM.
... A phase I clinical study showed that a low dose gamma interferon prior to edrocolomab was superior to a high dose in augmenting monocyte mediated ADCC (204). A phase II study in advanced colorectal cancer (205) found that purified monocytes, lymphocytes and NK cells obtained from treated patients had enhanced activity, but no objective responses were seen. Radiolabelled edrocolomab was used and imaging or immunoperoxidase staining of biopsied tissue showed that the antibody did not always reach all metastatic sites. ...
There has been much progress in the understanding of the relationship between the immune system and colorectal cancer. This has led to the use of immunomodulatory therapy in the adjuvant and palliative treatment of the condition. Although attempts at the use of non-specific immunomodulation with agents such as levamisole, cimetidine, alpha interferon and Bacillus Calmette-Guerin (BCG) have not produced significant clinical benefits when tested in randomized trials in both the adjuvant setting and for metastatic disease, promising results are being obtained with more specific therapy. Edrecolomab [corrected], a murine monoclonal antibody targeting the 17-1A antigen on malignant colorectal cells has produced a reduction in relapse and mortality rates when used as adjuvant treatment following surgery for Dukes' C colon cancer. Active specific therapy with autologous tumour vaccine administered with BCG has produced similar benefits in Dukes' B cancer. Both 3H1 anti-idiotypic antibody against carcinoembryonic antigen and 105AD7 antibody to gp72 glycoprotein have demonstrated in-vitro and in-vivo immune activation against tumour. Non-randomized studies postulate prolongation of survival using these antibodies in advanced disease. These agents are all currently being tested in randomized studies powered to detect meaningful survival differences and clinical benefit. Immune therapy offers the potential of low toxicity therapy in colorectal cancer and may have a role as an adjunct to conventional chemotherapy.
The chapter reviews the various ongoing attempts to incorporate mechanistic assessments into Phase I trials, and suggests the steps for their improvement. Because of the nature of the mechanisms of action of newer anticancer agents, it is logical to begin to build in novel end points, such as the determination of saturation dose (SD), by incorporating pharmacodynamic end points. To fully exploit the potential of the new anticancer agents, it may be necessary to develop the concept of an SD, at which the target is 99% inhibited, as well as a conventional maximum tolerated dose. The development of assays to allow determination of expression of target protein in biopsy samples from tumors, plus the advances in noninvasive methods such as positron emission tomography (PET) can help in determining SD. Mechanism-oriented studies over a range of doses could address important questions central to oncology. This method could potentially be used to monitor the biological mechanism of the action of topo I inhibitors, perhaps even allowing estimation of synergistic effects with other agents.
The feasibility of combining the Lym-1 monoclonal antibody (MoAb) with interferon-gamma (IFN-gamma) in the treatment of chronic lymphocytic leukemia (CLL) was evaluated. We used an in vitro tumor lysis model that incorporated fresh CLL cells from 21 different patients as targets for two distinct normal human leukocyte effector subsets, neutrophils, and peripheral blood mononuclear cells (PBMCs). Lym-1 antigen (Lym-1- Ag) expression varied greatly and did not correlate with the expression of other CLL-associated antigens such as CD5, CD19, or HLA-DR. CLL cells were not lysed by neutrophils alone or with IFN-gamma in the absence of Lym-1. Neutrophil Lym-1-dependent cytotoxicity (ADCC) in the absence of IFN-gamma was weak and inconsistent. IFN-gamma exposure induced MoAb-dependent lysis of 80% of 21 CLL targets and resulted in an eightfold augmentation of neutrophil ADCC against the remainder. Cytotoxicity correlated directly and positively with Lym-1-Ag expression. Confirmation of the need for interaction between neutrophil IgG Fc receptors (Fc gamma Rs) and the Fc portion of the Lym-1 MoAb was obtained by demonstrating that purified Staphylococcus aureus Protein A (SpA) inhibited ADCC. IFN-gamma exposure caused no consistent alternations in Lym-1-Ag expression on CLL cells so that target antigen upregulation was unlikely to account for augmentation of neutrophil ADCC. PBMCs alone, exposed to interkeukin-2 (IL-2) or IFN-gamma, or with Lym-1 in the presence or absence of IL-2 or IFN-gamma were unable to lyse CLL targets. PBMCs were able to kill Raji Burkitt lymphoma cells in conjunction with Lym-1, so their ability to interact with Lym- 1-coated targets and their lytic functions appeared intact. These results emphasize the importance of examining fresh tumor cells with different leukocyte effector subsets before designing a clinical trial that combines a therapeutic MoAb with a cytokine.
Current therapy for ovarian cancer typically involves indiscriminate chemotherapies that can have severe off target effects on healthy tissue and are still plagued by aggressive recurrence. Recent shifts towards targeted therapies offer the possibility of circumventing the obstacles experienced by these traditional treatments. While antibodies are the pioneering agents in targeted therapies, clinical experience has demonstrated that their antitumor efficacy is limited due to their high immunogenicity, large molecular size, and costly and laborious production. In contrast, nucleic acid based chemical antibodies, also known as aptamers, are ideal for this application given their small size, lack of immunogenicity and in vitro production. As aptamers have begun to demonstrate their promise through targeting Epithelial Cell Adhesion Molecule (EpCAM), as well as a number of ovarian cancer biomarkers, in in vivo and in vitro models, their clinical applicability is slowly being realised. This review explores some of the current progress of aptamers targeting cancer biomarkers and their potential role as ovarian cancer therapeutics.
The 1990s will witness a burgeoning number of biologicals under clinical investigation, either singly or in combination with other biologicals or chemotherapeutic agents. Already, biotherapies have demonstrated efficacy against certain malignancies. It is expected that their assimilation into our standard anticancer armamentarium will continue to broaden in the 1990s, leading to the dominance of biotherapy in cancer treatment soon after the year 2000. This chapter will summarize disease-related activity for selected biotherapies as we complete the final decade of this millennium.
Das Konzept, Tumorzellen mit Hilfe von Antikörpern gezielt zu markieren und zu eliminieren, geht auf Paul Ehrlich zurück, der schon vor ca. 90 Jahren die Vision von Antikörpern als „Zauberkugeln“ entwickelte, die ihr Ziel selbst finden [6]. In den Jahren zwischen 1958 und 1978 wurde eine Reihe von Untersuchungen publiziert, die über den Einsatz polyklonaler Antikörper in der Behandlung maligner Erkrankungen berichtete [15]. Jedoch erst die Entwicklung der Hybridomtechnik durch Köhler und Milstein [23] im Jahre 1975 ermöglichte die Produktion muriner monoklonaler Antikörper, die mit hoher Spezifität tumorassoziierte Antigene auf oder in Tumorzellen erfassen konnten und die sich in großen Mengen produzieren ließen. Diese revolutionierende Technik erweckte von neuem das Interesse an einer „Serotherapie“ maligner Erkrankungen.
Oncolytic herpes simplex virus (HSV) vectors have attracted increasing attention as novel anti-cancer agents. HSV entry is triggered by the binding of glycoprotein D (gD) to its receptors, such as herpesvirus entry mediator or nectin-1. We have recently reported the construction of a fully retargeted HSV platform that incorporates single-chain antibodies (scFv) into gD to mediate entry exclusively via tumor-associated antigens. In this study, we created an scFv directed against epithelial cell adhesion molecule (EpCAM), a recognized carcinoma-associated antigen, and inserted it into the retargeted HSV platform that is ablated for gD recognition of its canonical receptors and contains the entry-enhancing mutations in gB we previously identified. We observed that both initial entry and subsequent cell-to-cell spread of the retargeted virus were stringently dependent on cellular EpCAM expression. Interestingly, the retargeted virus developed larger plaques on some of the human tumor lines tested than the control virus bearing wild-type gD. Intratumoral injection of the retargeted virus revealed anti-tumor activity in a mouse xenograft model. These observations illustrate the versatility of our retargeted HSV platform as it allows expansion of the oncolytic virus toolbox for the treatment of diverse cancers.Gene Therapy accepted article preview online, 23 February 2016. doi:10.1038/gt.2016.17.
This chapter discusses the test results of cardiovascular toxicity such as amsacrine (m-amsa), doxorubiein (adriamycin), epirubicin, esorubicin, 5-fluoroeraeil (5-fu), interferon, mitomycin (mitomycin c), mitoxantrone (mitozantrone), thrombosis, and vascular. There is also some discussion on pulmonary toxicity in bleomycin, busulfan, cyelophosphamide, methotrexate, mitomyein (mitomyein C).. The chapter also discusses neurotoxicity, hematological toxicity, hepatotoxicity in L-asparaginase, cisplatin (CDDP), high-dose cisplatin (CDDP), etoposide, ifosfamide, interferon, high-dose methotrexate, mitoxantrone (mitozantrone), and vincristine. Gastrointestinal toxicity in oral, antiemeties, high-dose methotrexate, pvb (cisplatin/vinblastine/bleomycin), and nephrotoxicity and other urinary system toxicity in carboplatin, cisplatin (CDDP), interferon, mitomycin (mytomyein C) have been examined. There is also some description of skin toxicity, ocular toxicity, ototoxicity, reproductive and sexual toxicity.
