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Trend of clinical trials on cell therapy worldwide and in China. (A) Newly initiated active clinical trials on cell therapy have increased especially after 2014, and the dominating type is converting from vaccine to CAR/TCR-T. (B) Newly initiated active clinical trials in China continue to increase since 2015, and the dominating type is CAR/TCR. (C) Newly initiated active clinical trials increase both in and outside of China (since 2015).
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Cell therapy is a distinguished targeted immunotherapy with great potential to treat solid tumors in the new era of cancer treatment. Cell therapy products include genetically engineered cell products and non-genetically engineered cell products. Several recent cell therapies, especially chimeric antigen receptor (CAR)-T cell therapies, have been a...
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Recent years have seen a marked increase in research on chimeric antigen receptor T (CAR-T) cells, with specific relevance to the treatment of hematological malignancies. Here, the structural principles, iterative processes, and target selection of CAR-T cells for therapeutic applications are described in detail, as well as the challenges faced in...
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Citations
... Recent years, chimeric antigen receptor (CAR) T-cell has been designed to recognize and eliminate tumor cells via bridging between tumor-associated antigens (TAAs) and has become a sound momentum of therapeutic potential in hematological malignancies clinical practice, particularly CD19 CAR-T cells therapy [3][4][5][6][7]. However, several CAR-T cells have been described in treatment of late-stage multifocal, bulky solid tumors in recent clinical studies [8,9], the responses are not consistent and less favorable, mainly for specific and Ivyspring International Publisher homogeneously expressed targets, and the existing strong heterogeneity of complex components within solid tumor [10,11], Therefore, new and active CAR-T cells with reliable safety and significant improvement in solid tumor treatments are urgently needed. ...
Background: Chimeric antigen receptor (CAR) T-cell therapy is practical in treating cancers of hematopoietic origin, but of that in solid tumors compromises efficacy for the loss of the antigen recognized by the CAR. However, dendritic cell (DC)/tumor fusion vaccines present a spectrum of known or unknown tumor antigens to stimulate T cell expansion and enhanced T cell response. Developing a new strategy of enhanced nanobody-based CAR-T (Nb-CAR-T) cells antitumor activity by DC/tumor fusion vaccines stimulation would provide guidance for more effective CAR-T cell therapies.
Methods: Considering the therapeutic potential of nanobody (Nb), we first screened EGFRvIII Nb, then constructed and verified the function of EGFRvIII Nb-CAR-T cells in vitro and in vivo. We further combined DC/tumor fusion vaccines to boost EGFRvIII Nb-CAR-T cells antitumor effect, which was evaluated in vitro Nb-CAR-T cell function and in the tumor-bearing xenograft mouse models.
Results: We had for the first time successfully selected EGFRvIII Nb for the generation of the novel EGFRvIII Nb-CAR-T cells. Importantly, our results suggested that DC/tumor fusion vaccines stimulate Nb-CAR-T cells response not only in improving T cell proliferation, T cell activation, cytokine secretion and tumor-specific cytotoxicity in vitro, but also significantly reducing tumor burden, prolonging survival and improving Nb-CAR-T cells infiltration.
Conclusions: We have innovatively shown that DC/tumor fusion vaccines significantly enhance the efficacy of Nb-CAR-T cells against solid tumors. This new strategy has provided a promising therapeutic platform for promoting the clinical treatment of CAR-T cells therapy.
... Despite all adversities, CAR-T cell therapy still has a high chance of successfully treating solid tumors. The key to effective CAR-T cell investigation in solid tumors, which has proven to be the most difficult, is identifying antigens exclusively expressed on the tumor cell surface [136]. Alongside finding exclusively expressed antigens on solid tumors' cell membranes, characterizing the diseases and directing the choice of the best treatment regimens should be made more accessible by tracking the reduction, migration, and proliferation of immune cells across the entire body [137]. ...
Cell therapy has reached significant milestones in various life-threatening diseases, including cancer. Cell therapy using fluorescent and radiolabeled chimeric antigen receptor (CAR)-T cell is a successful strategy for diagnosing or treating malignancies. Since cell therapy approaches have different results in cancers, the success of hematological cancers has yet to transfer to solid tumor therapy, leading to more casualties. Therefore, there are many areas for improvement in the cell therapy platform. Understanding the therapeutic barriers associated with solid cancers through cell tracking and molecular imaging may provide a platform for effectively delivering CAR-T cells into solid tumors. This review describes CAR-T cells' role in treating solid and non-solid tumors and recent advances. Furthermore, we discuss the main obstacles, mechanism of action, novel strategies and solutions to overcome the challenges from molecular imaging and cell tracking perspectives.
... In 2021, further, development made four new promising CD19CARs available, Breyanzi, Yescarta, Kymriah and Tecartus, as well as a CAR targeting B cell maturation antigen (BCMA) in myeloma, Abecma and Carvykti (CAR T Cells, 2023). In contrast, solid tumours patients have so far benefited less from CAR therapy despite the high number of clinical trials run worldwide (Sterner and Sterner, 2021;Chen et al., 2022;Del Bufalo et al., 2023). Indeed, several challenges hampering CAR T cell efficacy have yet to be overcome and include i) poor target recognition, ii) low tumour infiltration, iii) suboptimal T cell activation and iv) lack of persistence on site (Guedan et al., 2019;Wagner et al., 2020;Marofi et al., 2021). ...
Adoptive transfer of T cells modified to express chimeric antigenic receptors (CAR) has emerged as a solution to cure refractory malignancies. However, although CAR T cell treatment of haematological cancers has now shown impressive improvement in outcome, solid tumours have been more challenging to control. The latter type is protected by a strong tumour microenvironment (TME) which might impact cellular therapeutic treatments. Indeed, the milieu around the tumour can become particularly inhibitory to T cells by directly affecting their metabolism. Consequently, the therapeutic cells become physically impeded before being able to attack the tumour. It is therefore extremely important to understand the mechanism behind this metabolic break in order to develop TME-resistant CAR T cells. Historically, the measurement of cellular metabolism has been performed at a low throughput which only permitted a limited number of measurements. However, this has been changed by the introduction of real-time technologies which have lately become more popular to study CAR T cell quality. Unfortunately, the published protocols lack uniformity and their interpretation become confusing. We herein tested the essential parameters to perform a metabolic study on CAR T cells and propose a check list of factors that should be set in order to draw sound conclusion.
... However, CAR T-cell therapy against solid tumors, which comprise about 90% of the total cancer landscape (6), has encountered very limited success. Notably, the clinical efficacy of CAR T-cell trials against the top three widely expressed solid tumor targets namely mesothelin (Meso), GPC3 and mucin-1 (MUC1) have so far been met with low to middling success (7). ...
... Here, we evaluated the effect of FAP CAR T-cell pre-treatment on therapeutic efficacy of CAR T-cells targeting tumor-antigens currently under investigation in clinical trials against solid tumors (7,8). For this purpose, we selected the tumor associated antigen (TAA) Mesothelin which is overexpressed in most solid tumors including mesothelioma and large sub-sets of ovarian, breast, pancreatic and lung adenocarcinomas (27). ...
Adoptive cell therapy based on chimeric antigen receptor (CAR)-engineered T-cells has proven to be lifesaving for many cancer patients. However, its therapeutic efficacy has so far been restricted to only a few malignancies, with solid tumors proving to be especially recalcitrant to efficient therapy. Poor intra-tumor infiltration by T cells and T cell dysfunction due to a desmoplastic, immunosuppressive microenvironment are key barriers for CAR T-cell success against solid tumors. Cancer-associated fibroblasts (CAFs) are critical components of the tumor stroma, evolving specifically within the tumor microenvironment (TME) in response to tumor cell cues. The CAF secretome is a significant contributor to the extracellular matrix and a plethora of cytokines and growth factors that induce immune suppression. Together they form a physical and chemical barrier which induces a T cell-excluding ‘cold’ TME. CAF depletion in stroma rich solid tumors can thus provide an opportunity to convert immune evasive tumors susceptible to tumor-antigen CAR T-cell cytotoxicity. Using our TALEN-based gene editing platform we engineered non-alloreactive, immune evasive CAR T-cells (termed UCAR T-cells) targeting the unique CAF marker Fibroblast Activation Protein, alpha (FAP). In an orthotopic mouse model of triple-negative breast cancer (TNBC) composed of patient derived-CAFs and tumor cells, we demonstrate the efficacy of our engineered FAP UCAR T-cells in CAF depletion, reduction of desmoplasia and successful tumor infiltration. Furthermore, while previously resistant, pre-treatment with FAP UCAR T-cells now sensitized these tumors to Mesothelin (Meso) UCAR T-cell infiltration and anti-tumor cytotoxicity. Combination therapy of FAP UCAR, Meso UCAR T cells and the checkpoint inhibitor anti-PD-1 significantly reduced tumor burden and prolonged mice survival. Our study thus proposes a novel treatment paradigm for successful CAR T-cell immunotherapy against stroma-rich solid tumors.
... Cell therapies are in common clinical practice for certain indications, such as islet cell transplants, and are also being aggressively developed in other areas of medicine, such as T-cell therapy of tumor. 66 Take T-cell therapy for tumor treatment as an example, chimeric antigen receptor (CAR) T cells are genetically engineered T cells to express a receptor for the recognition of the particular surface marker that has given rise to advances in the treatment of blood disorders. However, their efficacy in solid tumor treatment has not yet been supported. ...
Introduction
The immunosuppressive tumor microenvironment (TME) of solid tumors inhibits most drug delivery system-based nanomaterials from achieving deep penetration in tumor tissue and interferes with T cell activity in terms of differentiation and exhaustion, which is becoming a critical therapy hurdle for solid tumors. Therefore, developing a therapeutic strategy with abilities of rapid establishment of tumor-targeted cells, elimination of immune obstacles, and enhanced active immunization is very important, while is still a big challenge.
Methods
A new strategy was explored to enhance immune therapy via the conjugation of microRNA155 (miR) to the surface of therapeutic monocyte with graphene quantum dots (GQDs).
Results
TME was reversed using surface-engineered monocyte immunotherapy via reprogramming pro-tumoral M2 TAMs into antitumor M1, and thus tumor elimination was dramatically enhanced.
Conclusion
Such a surface-engineered monocyte immunotherapy has been demonstrated to be well tolerated to intravenous administration and bio-compatible, showing the potential to be extended for the solid tumor treatment.
Multiple myeloma (MM), a malignancy of plasma cells, is an incurable disease that is characterized by the neoplastic proliferation of plasma cells leading to extensive skeletal destruction. This includes osteolytic lesions, osteopenia, and pathologic fractures. MM is clinically manifested through bone pain, renal insufficiency, hypercalcemia, anemia, and recurrent infections. Its prevalence and the need for effective treatment underscore the importance of this research.
Recent advancements in MM therapy have been significant, particularly with the integration of daratumumab into first-line treatments. The use of daratumumab in regimens such as DRD (Daratumumab, Revlimid, Dexamethasone) and D-RVd (Daratumumab, Lenalidomide, Bortezomib, Dexamethasone) represents a paradigm shift in the treatment landscape. GRIFFIN and CASSIOPEIA trials have highlighted the efficacy of these regimens, particularly in prolonging progression-free survival and deepening patient responses. The shift from older regimens like MPV (Melphalan, Prednisone, Velcade) to more effective ones like DRD and RVD has been pivotal in treatment strategies.
This review also focuses on the potential of Chimeric Antigen Receptor T-cell therapy and bispecific antibodies in MM. CAR-T therapy, which has shown success in other hematological malignancies, is being explored for its ability to specifically target MM cells. The latest clinical trials and research findings are analyzed to evaluate the efficacy and challenges of CAR-T therapy in MM. Additionally, the role of bispecific antibodies, which are designed to bind both cancer cells and T cells, is explored. These antibodies offer a unique mechanism that could complement the effects of CAR-T therapy.
Over 100 innovative in vitro transcribed (IVT)-mRNAs are presently undergoing clinical trials, with a projected substantial impact on the pharmaceutical market in the near future. Τhe idea behind this is that after the successful cellular internalization of IVT-mRNAs, they are subsequently translated into proteins with therapeutic or prophylactic relevance. Simultaneously, cancer immunotherapy employs diverse strategies to mobilize the immune system in the battle against cancer. Therefore, in this review, the fundamental principles of IVT-mRNA to its recruitment in cancer immunotherapy, are discussed and analyzed. More specifically, this review paper focuses on the development of mRNA vaccines, the exploitation of neoantigens, as well as Chimeric Antigen Receptor (CAR) T-Cells, showcasing their clinical applications and the ongoing trials for the development of next-generation immunotherapeutics. Furthermore, this study investigates the synergistic potential of combining the CAR immunotherapy and the IVT-mRNAs by introducing our research group novel, patented delivery method that utilizes the Protein Transduction Domain (PTD) technology to transduce the IVT-mRNAs encoding the CAR of interest into the Natural Killer (NK)-92 cells, highlighting the potential for enhancing the CAR NK cell potency, efficiency, and bioenergetics. While IVT-mRNA technology brings exciting progress to cancer immunotherapy, several challenges and limitations must be acknowledged, such as safety, toxicity, and delivery issues. This comprehensive exploration of IVT-mRNA technology, in line with its applications in cancer therapeutics, offers valuable insights into the opportunities and challenges in the evolving landscape of cancer immunotherapy, setting the stage for future advancements in the field.
In solid tumors, three main complementary approaches of adoptive T cell therapies were successively developed: tumor infiltrating lymphocytes (TILs), chimeric antigen receptor (CAR) engineered T cells and high-affinity T cell receptor (TCR) engineered T cells. In this review, we summarized rational and main results of these three adoptive T cell therapies in solid tumors field and gave an overview of encouraging data and their limits. Then, we listed the major remaining challenges (including tumor antigen loss, on target/off tumor effect, tumor access difficulties and general / local immunosubversion) and their lines of research. Finally, we gave insight into the ongoing trials in solid tumor.
