Determinants of response and mechanisms of resistance of CAR T-cell therapy in multiple myeloma.
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ABSTRACT:
SUBMITTER: van de Donk NWCJ
PROVIDER: S-EPMC8357299 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Despite the substantial improvement of therapeutic approaches, multiple myeloma (MM) remains mostly incurable. However, immunotherapeutic and especially T cell-based approaches pioneered the therapeutic landscape for relapsed and refractory disease recently. Targeting B-cell maturation antigen (BCMA) on myeloma cells has been demonstrated to be highly effective not only by antibody-derived constructs but also by adoptive cellular therapies. Chimeric antigen receptor (CAR)-transgenic T cells lead to deep, albeit mostly not durable responses with manageable side-effects in intensively pretreated patients. The spectrum of adoptive T cell-transfer covers synthetic CARs with diverse specificities as well as currently less well-established T cell receptor (TCR)-based personalized strategies. In this review, we want to focus on treatment characteristics including efficacy and safety of CAR- and TCR-transgenic T cells in MM as well as the future potential these novel therapies may have. ACT with transgenic T cells has only entered clinical trials and various engineering strategies for optimization of T cell responses are necessary to overcome therapy resistance mechanisms. We want to outline the current success in engineering CAR- and TCR-T cells, but also discuss challenges including resistance mechanisms of MM for evading T cell therapy and point out possible novel strategies.
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Project description:Although treatment outcomes of multiple myeloma patients have improved significantly during the last two decades, myeloma is still an incurable disease. There are newly emerging immunotherapies to treat multiple myeloma including monoclonal antibodies, antibody-drug conjugate, bispecific antibodies, and chimeric antigen receptor (CAR) T cell therapy. Impressive response rate and clinical efficacy in heavily pretreated myeloma patients led to the FDA approval of the first myeloma CAR-T therapy in March 2021. Among many different targets for myeloma CAR-T therapies, B Cell Maturation Antigen (BCMA) has been the most successful target so far, but other targets which can be used either for single-target or dual-target CAR-T's are actively being explored. Clinical efficacy and safety of current myeloma CAR-T therapies will be presented here. Potential mechanisms leading to resistance include clearance of CAR-T cells, antigenic escape, and immunosuppressive tumor microenvironment. Novel strategies to enhance myeloma CAR-T will also be described. In this article, we provide a comprehensive review of the current data and the future directions of myeloma CAR-T therapies.
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Project description:The successes with chimeric antigen receptor (CAR) T cell therapy in early clinical trials involving patients with pre-B cell acute lymphoblastic leukaemia (ALL) or B cell lymphomas have revolutionized anticancer therapy, providing a potentially curative option for patients who are refractory to standard treatments. These trials resulted in rapid FDA approvals of anti-CD19 CAR T cell products for both ALL and certain types of B cell lymphoma - the first approved gene therapies in the USA. However, growing experience with these agents has revealed that remissions will be brief in a substantial number of patients owing to poor CAR T cell persistence and/or cancer cell resistance resulting from antigen loss or modulation. Furthermore, the initial experience with CAR T cells has highlighted challenges associated with manufacturing a patient-specific therapy. Understanding the limitations of CAR T cell therapy will be critical to realizing the full potential of this novel treatment approach. Herein, we discuss the factors that can preclude durable remissions following CAR T cell therapy, with a primary focus on the resistance mechanisms that underlie disease relapse. We also provide an overview of potential strategies to overcome these obstacles in an effort to more effectively incorporate this unique therapeutic strategy into standard treatment paradigms.
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Project description:Antibodies targeting CD38 are rapidly changing the treatment landscape of multiple myeloma (MM). CD38-directed antibodies have several mechanisms of action. Fc-dependent immune effector mechanisms include complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and apoptosis. In addition, direct effects and immunomodulatory effects contribute to the efficacy of CD38-directed antibodies. Daratumumab, the first-in-class anti-CD38 monoclonal antibody, is now part of standard treatment regimens of both newly diagnosed as well as relapsed/refractory MM patients. The FDA has recently approved isatuximab in combination with pomalidomide and dexamethasone for relapsed/refractory MM patients after at least two prior therapies. Further, the other CD38-targeting antibodies (i.e., MOR202 and TAK-079) are increasingly used in clinical trials. The shift to front-line treatment of daratumumab will lead to an increase in patients refractory to CD38 antibody therapy already after first-line treatment. Therefore, it is important to gain insight into the mechanisms of resistance to CD38-targeting antibodies in MM, and to develop strategies to overcome this resistance. In the current review, we will briefly describe the most important clinical data and mechanisms of action and will focus in depth on the current knowledge on mechanisms of resistance to CD38-targeting antibodies and potential strategies to overcome this.
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Project description:The emergence of various novel therapies over the last decade has changed the therapeutic landscape for multiple myeloma. While the clinical outcomes have improved significantly, the disease remains incurable, typically in patients with relapsed and refractory disease. Chimeric antigen receptor (CAR) T-cell therapies have achieved remarkable clinical success in B-cell malignancies. This scope of research has more recently been extended to the field of myeloma. While B-cell maturation antigen (BCMA) is currently the most well-studied CAR T antigen target in this disease, many other antigens are also undergoing intensive investigations. Some studies have shown encouraging results, whereas some others have demonstrated unfavorable results due to reasons such as toxicity and lack of clinical efficacy. Herein, we provide an overview of CAR T-cell therapies in myeloma, highlighted what has been achieved over the past decade, including the latest updates from ASH 2020 and discussed some of the challenges faced. Considering the current hits and misses of CAR T therapies, we provide a comprehensive analysis on the current manufacturing technologies, and deliberate on the future of CAR T-cell domain in MM.
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Project description: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.
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Project description:AbstractMultiple myeloma is characterized by frequent clinical relapses after conventional therapy. Recently, chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA) has been established as a treatment option for patients with relapsed or refractory disease. However, although >70% of patients initially respond to this treatment, clinical relapse and disease progression occur in most cases. Recent studies showed persistent expression of BCMA at the time of relapse, indicating that immune-intrinsic mechanisms may contribute to this resistance. Although there were no preexisting T-cell features associated with clinical outcomes, we found that patients with a durable response to CAR T-cell treatment had greater persistence of their CAR T cells than patients with transient clinical responses. They also possessed a significantly higher proportion of CD8+ T-effector memory cells. In contrast, patients with short-lived responses to treatment have increased frequencies of cytotoxic CD4+ CAR T cells. These cells expand in vivo early after infusion but express exhaustion markers (hepatitis A virus cellular receptor 2 [HAVCR2] and T-cell immunoglobulin and mucin domain-containing-3 [TIGIT]) and remain polyclonal. Finally, we demonstrate that nonclassical monocytes are enriched in the myeloma niche and may induce CAR T-cell dysfunction through mechanisms that include transforming growth factor β. These findings shed new light on the role of cytotoxic CD4+ T cells in disease progression after CAR T-cell therapy.
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Project description:Intratumor heterogeneity as a clinical challenge becomes most evident after several treatment lines, when multidrug-resistant subclones accumulate. To address this challenge, the characterization of resistance mechanisms at the subclonal level is key to identify common vulnerabilities. In this study, we integrate whole-genome sequencing, single-cell (sc) transcriptomics (scRNA sequencing), and chromatin accessibility (scATAC sequencing) together with mitochondrial DNA mutations to define subclonal architecture and evolution for longitudinal samples from 15 patients with relapsed or refractory multiple myeloma. We assess transcriptomic and epigenomic changes to resolve the multifactorial nature of therapy resistance and relate it to the parallel occurrence of different mechanisms: (1) preexisting epigenetic profiles of subclones associated with survival advantages, (2) converging phenotypic adaptation of genetically distinct subclones, and (3) subclone-specific interactions of myeloma and bone marrow microenvironment cells. Our study showcases how an integrative multiomics analysis can be applied to track and characterize distinct multidrug-resistant subclones over time for the identification of molecular targets against them.
2023-08-01 | GSE235783 | GEO
Project description:BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.
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