Adoptive T cell therapy of solid tumors: time to team up with immunogenic chemo/radiotherapy.
TL;DR: In this article, the authors highlight the beneficial effects of combining ACT with conventional chemo and/or radiotherapy, while originally classified as immunosuppressive, these methodologies can also promote the engraftment of ACT products, immunogenic cell death, and the reprogramming of more favorable microenvironments.
About: This article is published in Current Opinion in Immunology.The article was published on 2022-02-01 and is currently open access. It has received 13 citations till now. The article focuses on the topics: Immunogenic cell death & Radiation therapy.
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TL;DR: This review focuses on the progress and challenges of CAR-T cell therapy in hematological malignancies, such as attractive therapeutic targets,CAR-T related toxicities, and resistance to CAR- T cell therapy, and provides some practical recommendations.
Abstract: Chimeric antigen receptor T (CAR-T) cell therapy represents a major breakthrough in cancer treatment, and it has achieved unprecedented success in hematological malignancies, especially in relapsed/refractory (R/R) B cell malignancies. At present, CD19 and BCMA are the most common targets in CAR-T cell therapy, and numerous novel therapeutic targets are being explored. However, the adverse events related to CAR-T cell therapy might be serious or even life-threatening, such as cytokine release syndrome (CRS), CAR-T-cell-related encephalopathy syndrome (CRES), infections, cytopenia, and CRS-related coagulopathy. In addition, due to antigen escape, the limited CAR-T cell persistence, and immunosuppressive tumor microenvironment, a considerable proportion of patients relapse after CAR-T cell therapy. Thus, in this review, we focus on the progress and challenges of CAR-T cell therapy in hematological malignancies, such as attractive therapeutic targets, CAR-T related toxicities, and resistance to CAR-T cell therapy, and provide some practical recommendations.
28 citations
TL;DR: The current literature studies and understanding of the parameters that affect the chimeric antigen receptor T cells (CAR-T's) activation, effector function, in vivo persistence, and antitumour effects are reviewed.
Abstract: Abstract In this article, we reviewed the current literature studies and our understanding of the parameters that affect the chimeric antigen receptor T cells (CAR-T's) activation, effector function, in vivo persistence, and antitumour effects. These factors include T cell subsets and their differentiation stages, the components of chimeric antigen receptors (CAR) design, the expression promoters and delivery vectors, and the CAR-T production process. The CAR signalling and CAR-T activation were also studied in comparison to TCR. The last section of the review gave special consideration of CAR design for solid tumours, focusing on strategies to improve CAR-T tumour infiltration and survival in the hostile tumour microenvironment. With several hundred clinical trials undergoing worldwide, the pace of CAR-T immunotherapy moves from bench to bedside is unprecedented. We hope that the article will provide readers a clear and comprehensive view of this rapidly evolving field and will help scientists and physician to design effective CAR-Ts immunotherapy for solid tumours.
7 citations
TL;DR: The present nanomaterial-based techniques provide a strong base for future therapeutic approaches for skin regeneration strategies in the treatment of diabetic wounds and emerging therapeutics such as bioengineered skin substitutes and nanomMaterial-based innovative approaches such as antibacterial hyperthermia therapy and gene therapy for the Treatment of DFUs are highlighted.
Abstract: Diabetes mellitus (DM) is a predominant chronic metabolic syndrome, resulting in various complications and high mortality associated with diabetic foot ulcers (DFUs). Approximately 15–30% of diabetic patients suffer from DFUs, which is expected to increase annually. The major challenges in treating DFUs are associated with wound infections, alterations to inflammatory responses, angiogenesis and lack of extracellular matrix (ECM) components. Furthermore, the lack of targeted therapy and efficient wound dressings for diabetic wounds often results in extended hospitalization and limb amputations. Hence, it is essential to develop and improve DFU-specific therapies. Nanomaterial-based innovative approaches have tremendous potential for preventing and treating wound infections of bacterial origin. They have greater benefits compared to traditional wound dressing approaches. In this approach, the physiochemical features of nanomaterials allow researchers to employ different methods for diabetic wound healing applications. In this review, the status and prevalence of diabetes mellitus (DM) and amputations due to DFUs in India, the pathophysiology of DFUs and their complications are discussed. Additionally, nanomaterial-based approaches such as the use of nanoemulsions, nanoparticles, nanoliposomes and nanofibers for the treatment of DFUs are studied. Besides, emerging therapeutics such as bioengineered skin substitutes and nanomaterial-based innovative approaches such as antibacterial hyperthermia therapy and gene therapy for the treatment of DFUs are highlighted. The present nanomaterial-based techniques provide a strong base for future therapeutic approaches for skin regeneration strategies in the treatment of diabetic wounds.
5 citations
TL;DR: In this paper , the authors discuss the limitations of CAR-T cell therapy in multiple myeloma (MM) patients, and summarize some optimization strategies to overcome these challenges, including optimizing CAR structure, such as utilizing dual-targeted/multi-targeted CAR-Ts and armored CART cells, optimizing manufacturing processes, combing CAR-t cell therapy with existing or emerging therapeutic approaches, and performing subsequent anti-myeloma therapy as salvage therapy or maintenance/consolidation therapy.
Abstract: Over the last decade, the survival outcome of patients with multiple myeloma (MM) has been substantially improved with the emergence of novel therapeutic agents, such as proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, selective inhibitors of nuclear export (SINEs), and T cell redirecting bispecific antibodies. However, MM remains an incurable neoplastic plasma cell disorder, and almost all MM patients inevitably relapse due to drug resistance. Encouragingly, B cell maturation antigen (BCMA)-targeted chimeric antigen receptor T (CAR-T) cell therapy has achieved impressive success in the treatment of relapsed/refractory (R/R) MM and brought new hopes for R/R MM patients in recent years. Due to antigen escape, the poor persistence of CAR-T cells, and the complicated tumor microenvironment, a significant population of MM patients still experience relapse after anti-BCMA CAR-T cell therapy. Additionally, the high manufacturing costs and time-consuming manufacturing processes caused by the personalized manufacturing procedures also limit the broad clinical application of CAR-T cell therapy. Therefore, in this review, we discuss current limitations of CAR-T cell therapy in MM, such as the resistance to CAR-T cell therapy and the limited accessibility of CAR-T cell therapy, and summarize some optimization strategies to overcome these challenges, including optimizing CAR structure, such as utilizing dual-targeted/multi-targeted CAR-T cells and armored CAR-T cells, optimizing manufacturing processes, combing CAR-T cell therapy with existing or emerging therapeutic approaches, and performing subsequent anti-myeloma therapy after CAR-T cell therapy as salvage therapy or maintenance/consolidation therapy.
2 citations
TL;DR: Based on the progress in therapeutic design, predictions can be made as to what the future holds for increasing the percentage of positive patient outcomes for optimized systems.
Abstract: For many years, cell-surface glycans (in particular, Tumor-Associated Carbohydrate Antigens, TACAs) have been the target of both passive and active anticancer immunotherapeutic design. Recent advances in immunotherapy as a treatment for a variety of malignancies has revolutionized anti-tumor treatment regimens. Checkpoint inhibitors, Chimeric Antigen Receptor T-cells, Oncolytic virus therapy, monoclonal antibodies and vaccines have been developed and many approvals have led to remarkable outcomes in a subset of patients. However, many of these therapies are very selective for specific patient populations and hence the search for improved therapeutics and refinement of techniques for delivery are ongoing and fervent research areas. Most of these agents are directed at protein/peptide epitopes, but glycans–based targets are gaining in popularity, and a handful of approved immunotherapies owe their activity to oligosaccharide targets. In addition, nanotechnology and nanoparticle-derived systems can help improve the delivery of these agents to specific organs and cell types based on tumor-selective approaches. This review will first outline some of the historical beginnings of this research area and subsequently concentrate on the last 5 years of work. Based on the progress in therapeutic design, predictions can be made as to what the future holds for increasing the percentage of positive patient outcomes for optimized systems.
2 citations
References
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TL;DR: The adoptive transfer of highly selected tumor-reactive T cells directed against overexpressed self-derived differentiation antigens after a nonmyeloablative conditioning regimen resulted in the persistent clonal repopulation of T cells in cancer patients, leading to regression of the patients' metastatic melanoma as well as to the onset of autoimmune melanocyte destruction.
Abstract: We report here the adoptive transfer, to patients with metastatic melanoma, of highly selected tumor-reactive T cells directed against overexpressed self-derived differentiation antigens after a nonmyeloablative conditioning regimen. This approach resulted in the persistent clonal repopulation of T cells in those cancer patients, with the transferred cells proliferating in vivo, displaying functional activity, and trafficking to tumor sites. This led to regression of the patients' metastatic melanoma as well as to the onset of autoimmune melanocyte destruction. This approach presents new possibilities for the treatment of patients with cancer as well as patients with human immunodeficiency virus-related acquired immunodeficiency syndrome and other infectious diseases.
2,828 citations
TL;DR: A case of the abscopal effect is reported in a patient with melanoma treated with ipilimumab and radiotherapy, with temporal associations of tumor shrinkage with antibody responses to the cancer-testis antigen NY-ESO-1, changes in peripheral-blood immune cells, and increases in antibodies to other antigens after radiotherapy.
Abstract: The abscopal effect is a phenomenon in which local radiotherapy is associated with the regression of metastatic cancer at a distance from the irradiated site. The abscopal effect may be mediated by activation of the immune system. Ipilimumab is a mono‑ clonal antibody that inhibits an immunologic checkpoint on T cells, cytotoxic T‑lymphocyte–associated antigen 4 (CTLA ‑ 4). We report a case of the abscopal effect in a patient with melanoma treated with ipilimumab and radiotherapy. Temporal associations were noted: tumor shrinkage with antibody responses to the cancer– testis antigen NY‑ ESO‑ 1, changes in peripheral‑ blood immune cells, and increases in antibody responses to other antigens after radiotherapy. (Funded by the National Institutes of Health and others.)
1,769 citations
TL;DR: Fractionated but not single-dose radiotherapy induces an abscopal effect when in combination with anti–CTLA-4 antibody in two preclinical carcinoma models.
Abstract: Purpose This study tested the hypothesis that the type of dose fractionation regimen determines the ability of radiotherapy to synergize with anti-CTLA-4 antibody. Experimental design TSA mouse breast carcinoma cells were injected s.c. into syngeneic mice at two separate sites, defined as a "primary" site that was irradiated and a "secondary" site outside the radiotherapy field. When both tumors were palpable, mice were randomly assigned to eight groups receiving no radiotherapy or three distinct regimens of radiotherapy (20 Gy x 1, 8 Gy x 3, or 6 Gy x 5 fractions in consecutive days) in combination or not with 9H10 monoclonal antibody against CTLA-4. Mice were followed for tumor growth/regression. Similar experiments were conducted in the MCA38 mouse colon carcinoma model. Results In either of the two models tested, treatment with 9H10 alone had no detectable effect. Each of the radiotherapy regimens caused comparable growth delay of the primary tumors but had no effect on the secondary tumors outside the radiation field. Conversely, the combination of 9H10 and either fractionated radiotherapy regimens achieved enhanced tumor response at the primary site (P Conclusions Fractionated but not single-dose radiotherapy induces an abscopal effect when in combination with anti-CTLA-4 antibody in two preclinical carcinoma models.
1,331 citations
TL;DR: It is shown that even in the absence of any adjuvant, tumor cells dying in response to anthracyclins can elicit an effective antitumor immune response that suppresses the growth of inoculated tumors or leads to the regression of established neoplasia.
Abstract: Systemic anticancer chemotherapy is immunosuppressive and mostly induces nonimmunogenic tumor cell death. Here, we show that even in the absence of any adjuvant, tumor cells dying in response to anthracyclins can elicit an effective antitumor immune response that suppresses the growth of inoculated tumors or leads to the regression of established neoplasia. Although both antracyclins and mitomycin C induced apoptosis with caspase activation, only anthracyclin-induced immunogenic cell death was immunogenic. Caspase inhibition by Z-VAD-fmk or transfection with the baculovirus inhibitor p35 did not inhibit doxorubicin (DX)-induced cell death, yet suppressed the immunogenicity of dying tumor cells in several rodent models of neoplasia. Depletion of dendritic cells (DCs) or CD8 + T cells abolished the immune response against DX-treated apoptotic tumor cells in vivo. Caspase inhibition suppressed the capacity of DX-killed cells to be phagocytosed by DCs, yet had no effect on their capacity to elicit DC maturation. Freshly excised tumors became immunogenic upon DX treatment in vitro, and intratumoral inoculation of DX could trigger the regression of established tumors in immunocompetent mice. These results delineate a procedure for the generation of cancer vaccines and the stimulation of anti-neoplastic immune responses in vivo.
1,182 citations
TL;DR: It is found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8+ T cell reactivity to self-tissue and tumor, and the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells.
Abstract: Depletion of immune elements before adoptive cell transfer (ACT) can dramatically improve the antitumor efficacy of transferred CD8 + T cells, but the specific mechanisms that contribute to this enhanced immunity remain poorly defined. Elimination of CD4 + CD25 + regulatory T (T reg) cells has been proposed as a key mechanism by which lymphodepletion augments ACT-based immunotherapy. We found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8 + T cell reactivity to self-tissue and tumor. Surprisingly, enhanced antitumor efficacy and autoimmunity was caused by increased function rather than increased numbers of tumor-reactive T cells, as would be expected by homeostatic mechanisms. The γ C cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of γ C cytokine–responsive endogenous cells using antibody or genetic means resulted in the enhanced antitumor responses similar to those seen after nonmyeloablative conditioning. These data indicate that lymphodepletion removes endogenous cellular elements that act as sinks for cytokines that are capable of augmenting the activity of self/tumor-reactive CD8 + T cells. Thus, the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells.
968 citations