Toxicities of Chimeric Antigen Receptor T Cell Therapy in Multiple Myeloma: An Overview of Experience From Clinical Trials, Pathophysiology, and Management Strategies
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SUBMITTER: Zhou X
PROVIDER: S-EPMC7793717 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and non-haematological malignancies. CAR-T-cell therapy can induce rapid and durable clinical responses, but is associated with unique acute toxicities, which can be severe or even fatal. Cytokine-release syndrome (CRS), the most commonly observed toxicity, can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan dysfunction; rarely, severe CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH). Neurotoxicity, termed CAR-T-cell-related encephalopathy syndrome (CRES), is the second most-common adverse event, and can occur concurrently with or after CRS. Intensive monitoring and prompt management of toxicities is essential to minimize the morbidity and mortality associated with this potentially curative therapeutic approach; however, algorithms for accurate and consistent grading and management of the toxicities are lacking. To address this unmet need, we formed a CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising investigators from multiple institutions and medical disciplines who have experience in treating patients with various CAR-T-cell therapy products. Herein, we describe the multidisciplinary approach adopted at our institutions, and provide recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy.
| S-EPMC6733403 | biostudies-literature
Project description:Multiple myeloma represents 2% of all new cancer diagnoses in the United Kingdom and accounts for 2% of all cancer deaths. In the past few decades, there have been huge improvements in life expectancy which have been driven by novel therapeutic agents, autologous stem cell transplants and intensified supportive care. This review will discuss the pathogenesis of multiple myeloma, current management approaches and the direction of future treatments. In addition, this review will highlight the high burden of symptoms that patients experience and therefore the great benefits that can be gained from specialist palliative care input.
| S-EPMC7065505 | biostudies-literature
Project description:Multiple myeloma (MM) is a nearly always incurable malignancy of plasma cells, so new approaches to treatment are needed. T-cell therapies are a promising approach for treating MM, with a mechanism of action different than those of standard MM treatments. Chimeric antigen receptors (CARs) are fusion proteins incorporating antigen-recognition domains and T-cell signaling domains. T cells genetically engineered to express CARs can specifically recognize antigens. Success of CAR-T cells (CAR-Ts) against leukemia and lymphoma has encouraged development of CAR-T therapies for MM. Target antigens for CARs must be expressed on malignant cells, but expression on normal cells must be absent or limited. B-cell maturation antigen is expressed by normal and malignant plasma cells. CAR-Ts targeting B-cell maturation antigen have demonstrated significant antimyeloma activity in early clinical trials. Toxicities in these trials, including cytokine release syndrome, have been similar to toxicities observed in CAR-T trials for leukemia. Targeting postulated CD19+ myeloma stem cells with anti-CD19 CAR-Ts is a novel approach to MM therapy. MM antigens including CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain are under investigation as CAR targets. MM is genetically and phenotypically heterogeneous, so targeting of >1 antigen might often be required for effective treatment of MM with CAR-Ts. Integration of CAR-Ts with other myeloma therapies is an important area of future research. CAR-T therapies for MM are at an early stage of development but have great promise to improve MM treatment.
| S-EPMC5731088 | biostudies-literature
Project description:Multiple myeloma (MM) is a malignant plasma cell disorder that remains incurable for most patients, as persistent clonal evolution drives new mutations which confer MM high-risk signatures and resistance to standard care. The past two decades have significantly refashioned the therapeutic options for MM, especially adoptive T cell therapy contributing to impressive response rate and clinical efficacy. Despite great promises achieved from chimeric antigen receptor T-cell (CAR-T) therapy, the poor durability and severe toxicity (cytokine release syndrome and neurotoxicity) are still huge challenges. Therefore, relapsed/refractory multiple myeloma (RRMM), characterized by the nature of clinicopathologic and molecular heterogeneity, is frequently associated with poor prognosis. B Cell Maturation Antigen (BCMA) is the most successful target for CAR-T therapy, and other potential targets either for single-target or dual-target CAR-T are actively being studied in numerous clinical trials. Moreover, mechanisms driving resistance or relapse after CAR-T therapy remain uncharacterized, which might refer to T-cell clearance, antigen escape, and immunosuppressive tumor microenvironment. Engineering CAR T-cell to improve both efficacy and safety continues to be a promising area for investigation. In this review, we aim to describe novel tumor-associated neoantigens for MM, summarize the data from current MM CAR-T clinical trials, introduce the mechanism of disease resistance/relapse after CAR-T infusion, highlight innovations capable of enhanced efficacy and reduced toxicity, and provide potential directions to optimize manufacturing processes.
| S-EPMC9814974 | biostudies-literature
Project description:Multiple myeloma (MM) is the second most common hematologic malignancy and remains incurable despite the advent of numerous new drugs such as proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies. There is an unmet need to develop novel therapies for refractory/relapsed MM. In the past few years, chimeric antigen receptor (CAR)-modified T cell therapy for MM has shown promising efficacy in preclinical and clinical studies. Furthermore, the toxicities of CAR-T cell therapy are manageable. This article summarizes recent developments of CAR-T therapy in MM, focusing on promising targets, new technologies, and new research areas. Additionally, a comprehensive overview of antigen selection is presented along with preliminary results and future directions of CAR-T therapy development.
| S-EPMC6873434 | biostudies-literature
Project description:Adoptive cell transfer using chimeric antigen receptors (CAR) has emerged as one of the most promising new therapeutic modalities for patients with relapsed or refractory B-cell malignancies. Thus far, results in patients with advanced solid tumors have proven disappointing. Constitutive tonic signaling in the absence of ligand is an increasingly recognized complication when deploying these synthetic fusion receptors and can be a cause of poor antitumor efficacy, impaired survival, and reduced persistence in vivo In parallel, ligand-dependent tonic signaling can mediate toxicity and promote T-cell anergy, exhaustion, and activation-induced cell death. Here, we review the mechanisms underpinning CAR tonic signaling and highlight the wide variety of effects that can emerge after making subtle structural changes or altering the methodology of CAR transduction. We highlight strategies to prevent unconstrained tonic signaling and address its deleterious consequences. We also frame this phenomenon in the context of endogenous TCR tonic signaling, which has been shown to regulate peripheral tolerance, facilitate the targeting of foreign antigens, and suggest opportunities to coopt ligand-dependent CAR tonic signaling to facilitate in vivo persistence and efficacy. Mol Cancer Ther; 17(9); 1795-815. ©2018 AACR.
| S-EPMC6130819 | biostudies-literature
Project description:ImportanceThe use of chimeric antigen receptor-T cell (CAR-T) therapy and bispecific antibodies in multiple myeloma is expanding, with encouraging early results. It is unknown if the current geographic distribution of CAR-T therapy and bispecific antibodies in multiple myeloma allows access for patients in need, especially for Black populations, which have a higher incidence of multiple myeloma.ObjectiveTo investigate if the current geographic distribution of CAR-T cell therapy and bispecific antibodies for multiple myeloma allows equitable access for Black patients with multiple myeloma.Design, setting, and participantsThis cross-sectional study of data from CAR-T therapy and bispecific antibodies multiple myeloma clinical trials for all available studies listed in ClinicalTrials.gov until January 31, 2022. Only studies with 1 or more open sites in the US were analyzed. Data were analyzed February 2022.ResultsA total of 162 clinical trials were found, and 69 analyzed-7896 participants were either enrolled or expected to enroll, with 4386 participants (55.5%) enrolled or to be enrolled in CAR-T therapies clinical trials. The vast majority of clinical trials (66 [96%]) were sponsored by industry, and there were 140 clinical trials sites. The mean number of sites per trial was 8.1 (7.8 for CAR-T trials [range, 1-30 trials] vs 8.7 for bispecific antibodies [range, 1-26 trials]). Only 35.9% of Black patients lived in a county with an open trial. For the 10 states with the highest proportion of Black residents (ranging from 18.6% to 41.4%), 6 of those states (60%) had no (3 states) or less than 3 clinical trial openings (3 states) for either a CAR-T or bispecific antibody study.Conclusions and relevanceIn this cross-sectional study, we found that the geographic distribution of clinical trials for CAR-T and bispecific antibodies may contribute to disparities in access to the most advanced clinical trials for new multiple myeloma therapies. Since most of the ongoing trials were sponsored by industry, regulating the distribution of clinical trial sites may reduce these inequities.
| S-EPMC9419017 | biostudies-literature
Project description:Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of B cell malignancies, improving patient survival and long-term remission. Nonetheless, over 50% of patients experience severe treatment-related toxicities including cytokine release syndrome (CRS) and neurotoxicity. Differences in severity of toxic side-effects among anti-CD19 CARs suggest that the choice of costimulatory domain makes a significant contribution to toxicity, but comparisons are complicated by additional differences in the hinge and transmembrane (TM) domains of the most commonly used CARs in the clinic, segments that have long been considered to perform purely structural roles. In this perspective, we examine clinical and preclinical data for anti-CD19 CARs with identical antigen-binding (FMC63) and signalling (CD3ζ) domains to unravel the contributions of different hinge-TM and costimulatory domains. Analysis of clinical trials highlights an association of the CD28 hinge-TM with higher incidence of CRS and neurotoxicity than the corresponding sequences from CD8, regardless of whether the CD28 or the 4-1BB costimulatory domain is used. The few preclinical studies that have systematically varied these domains similarly support a strong and independent role for the CD28 hinge-TM sequence in high cytokine production. These observations highlight the value that a comprehensive and systematic interrogation of each of these structural domains could provide toward developing fundamental principles for rational design of safer CAR-T cell therapies.
| S-EPMC7794933 | biostudies-literature
Project description:Current clinical outcomes using chimeric-antigen receptors (CARs) against multiple myeloma show promise in the eradication of bulk disease. However, these anti-BCMA (CD269) CARs observe relapse as a common phenomenon after treatment due to the reemergence of either antigen-positive or -negative cells. Hence, the development of improvements in CAR design to target antigen loss and increase effector cell persistency represents a critical need. Here, we report on the anti-tumor activity of a CAR T-cell possessing two complete and independent CAR receptors against the multiple myeloma antigens BCMA and CS1. We determined that the resulting compound CAR (cCAR) T-cell possesses consistent, potent and directed cytotoxicity against each target antigen population. Using multiple mouse models of myeloma and mixed cell populations, we are further able to show superior in vivo survival by directed cytotoxicity against multiple populations compared to a single-expressing CAR T-cell. These findings indicate that compound targeting of BCMA and CS1 on myeloma cells can potentially be an effective strategy for augmenting the response against myeloma bulk disease and for initiation of broader coverage CAR therapy.
| S-EPMC5808076 | biostudies-literature
Project description:A patient with refractory multiple myeloma received an infusion of CTL019 cells, a cellular therapy consisting of autologous T cells transduced with an anti-CD19 chimeric antigen receptor, after myeloablative chemotherapy (melphalan, 140 mg per square meter of body-surface area) and autologous stem-cell transplantation. Four years earlier, autologous transplantation with a higher melphalan dose (200 mg per square meter) had induced only a partial, transient response. Autologous transplantation followed by treatment with CTL019 cells led to a complete response with no evidence of progression and no measurable serum or urine monoclonal protein at the most recent evaluation, 12 months after treatment. This response was achieved despite the absence of CD19 expression in 99.95% of the patient's neoplastic plasma cells. (Funded by Novartis and others; ClinicalTrials.gov number, NCT02135406.).
| S-EPMC4646711 | biostudies-literature