Recent updates on CAR T clinical trials for multiple myeloma.
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ABSTRACT:
SUBMITTER: Lin Q
PROVIDER: S-EPMC6829852 | biostudies-literature | 2019 Nov
REPOSITORIES: biostudies-literature
Publications
Recent updates on CAR T clinical trials for multiple myeloma.
Lin Quande Q Zhao Juanjuan J Song Yongping Y Liu Delong D
Molecular cancer 20191105 1
Proteasome inhibitors, immunomodulatory agents and monoclonal antibodies have dramatically changed the natural history of multiple myeloma (MM). However, most patients eventually suffer a relapse and succumb to the disease. Chimeric antigen receptor (CAR) engineered T cells targeting B cell maturation antigen (BCMA), CD138, CS1 glycoprotein antigen (SLAMF7) and light chains are in active development for therapy of refractory /relapsed (RR) MM. CD19- targeted CAR T cells in conjunction with autol ...[more]
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Project description: Not available
| S-EPMC10546715 | biostudies-literature
Project description:Background: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T-cell therapy is an emerging treatment option for multiple myeloma. The aim of this systematic review and meta-analysis was to determine its safety and clinical activity and to identify factors influencing these outcomes.Methods: We performed a database search using the terms "BCMA," "CAR," and "multiple myeloma" for clinical studies published between 01/01/2015 and 01/01/2020. The methodology is further detailed in PROSPERO (CRD42020125332).Results: Twenty-three different CAR-T-cell products have been used so far in 640 patients. Cytokine release syndrome was observed in 80.3% (69.0-88.2); 10.5% (6.8-16.0) had neurotoxicity. A higher neurotoxicity rate was reported in studies that included more heavily pretreated patients: 19.1% (13.3-26.7; I2?=?45%) versus 2.8% (1.3-6.1; I2?=?0%) (p?<?0.0001). The pooled overall response rate was 80.5% (73.5-85.9); complete responses (CR) were observed in 44.8% (35.3-54.6). A pooled CR rate of 71.9% (62.8-79.6; I2?=?0%) was noted in studies using alpaca/llama-based constructs, whereas it was only 18.0% (6.5-41.1; I2?=?67%) in studies that used retroviral vectors for CAR transduction. Median progression-free survival (PFS) was 12.2 (11.4-17.4) months, which compared favorably to the expected PFS of 1.9 (1.5-3.7) months (HR 0.14; p?<?0.0001).Conclusions: Although considerable toxicity was observed, BCMA-targeted CAR-T-cell therapy is highly efficacious even in advanced multiple myeloma. Subgroup analysis confirmed the anticipated inter-study heterogeneity and identified potential factors contributing to safety and efficacy. The results of this meta-analysis may assist the future design of CAR-T-cell studies and lead to optimized BCMA CAR-T-cell products.
| S-EPMC7713173 | biostudies-literature
Project description:There have been major recent advancements in the understanding and management of multiple myeloma. Diagnostic criteria have been revised and former ultra-high-risk smoldering multiple myeloma is now considered multiple myeloma in need of treatment. Understanding clonal progression, evolution, and tides not only has helped elucidate the disease behavior but might help expand therapeutic choices in order to select appropriate treatment for patients. Unprecedented response rates with modern triplet induction therapies containing proteasome inhibitor and immunomodulators have made this approach standard for initial treatment. The US Food and Drug Administration approved four new drugs (two targeted antibodies and two oral agents) in 2015 in relapsed/refractory multiple myeloma and these drugs along with the other already-available drugs have now increased the choices of regimens. Even drugs without single-agent activity, such as panobinostat and elotuzumab, have an important role, especially in the proteasome inhibitor refractory setting. Recent studies done in the context of novel agent induction suggest that high-dose therapy followed by autologous transplant continues to improve response rates and progression-free survival, thus underscoring their role in transplant-eligible patients. Evolving paradigms in the treatment of multiple myeloma include newer promising immune approaches, such as adoptive cellular therapies, vaccines, or antibody-based immune manipulations. Though multiple myeloma is still considered incurable, it is clear that with the improved understanding of disease biology and clonal architecture of relapse combined with the availability of multi-targeted approaches, we are ever closer to a lasting cure or transformation into indolent and long-lasting disease courses or both.
| S-EPMC4995679 | biostudies-literature
Project description:Background The prognosis of relapsed/refractory multiple myeloma (RRMM) patients with the extramedullary disease was significantly poor. Extramedullary multiple myeloma (EMM) patients gained limited benefits from traditional drugs. Anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy seems to be a promising approach to treat RRMM patients. However, very few clinical studies are designed for EMM. Our study aimed to compare and assess the safety, efficacy, and pharmacokinetics of anti-BCMA CAR-T cell therapy in EMM and non-EMM. Methods The results from published anti-BCMA CAR-T clinical trials, in which raw data of EMM patients were available, were reviewed and summarized. Two trials conducted in our clinical centers were analyzed and presented with detailed data. Results According to published anti-BCMA CAR-T clinical trials, the ORR of EMM ranged from 57% to 100%, with the complete remission (CR) rate of 29% to 60%. Between February 22, 2017, and September 26, 2019, a total of 61 subjects (EMM 25; non-EMM 36) received anti-BCMA CAR-T cell infusion. The data-cutoff date was April 1, 2021. There were no statistical differences between EMM and non-EMM groups in adverse events (AEs), including cytokine release syndrome (CRS). The most common AEs of grade ≥ 3 in both groups were hematologic toxicities. There was no significant difference in the objective response rate (ORR) and ≥ complete remission (CR) rate between both groups. However, the ≥ CR rate of the EMM group was lower than the non-EMM group receiving the fully human anti-BCMA CAR-T cell therapy (p = 0.026). The median progression-free survival (PFS) for EMM and the non-EMM group was 121 days and 361 days, respectively (p = 0.001). The median overall survival (OS) for EMM and the non-EMM group was 248 days and 1024 days, respectively (p = 0.005). The Cmax and AUC0-28d for EMM group were lower than non-EMM group (Cmax, p = 0.016; AUC0-28d, p = 0.016). Extramedullary disease was an independent prognostic risk factor for PFS (hazard ratio, 2.576; 95% CI, 1.343 to 4.941; p = 0.004) and OS (hazard ratio, 2.312; 95% CI, 1.165 to 4.592; p = 0.017) in RRMM patients receiving anti-BCMA CAR-T cell therapy. Conclusions Based on our results, EMM patients could benefit from the two anti-BCMA CAR products, although they had a shorter PFS and OS compared with non-EMM patients. Clinical Trial Registration http://www.chictr.org.cn, identifier ChiCTR-OPC-16009113 and ChiCTR1800018137.
| S-EPMC8589080 | biostudies-literature
Project description:Multiple myeloma (MM) is a haematologic malignancy with significant improvements in the overall survival over the last decade. However, patients still relapse and die due to a lack of treatment options. Ultimately, novel therapies with the potential for long term remissions are needed for patients with advanced MM. Research efforts for such immune therapies were not successful until recently when the first immunotherapies for MM were approved in 2015 and many more are under development. In this review, we focus on adoptive cell therapies including CAR T-cell and CAR NK-cell therapies for patients with MM. We will provide an update on clinical and translational advances with a focus on results from ongoing clinical trials with BCMA targeted cellular therapies and the development of other novel targets, changes in the manufacturing process, trials focusing on earlier lines of therapy and combinations with other therapies as well as off the shelf products.
| S-EPMC7137578 | biostudies-literature
Project description:Despite the significant improvement in survival outcomes of multiple myeloma (MM) over the past decade, it remains an incurable disease. Patients with triple-class refractory MM have limited treatment options and a dismal prognosis. Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen has transformed the treatment armamentarium of relapsed/refractory MM (RRMM), with unprecedented overall response rates in this difficult-to-treat patient population. However, a significant proportion of patients ultimately relapse despite achieving deep remission. Several innovative approaches, including alternative/dual-antigen-specific CAR T-cell constructs, genetically engineered "off-the-shelf" CAR T cells, and strategies to counteract an immunosuppressive microenvironment, may dramatically reshape the field of CAR T-cell therapy in the future. These strategies are being actively investigated in preclinical and early clinical trial settings with the hopes of enhancing the durability of responses and, thereby, improving the overall survival of RRMM patients after CAR T-cell therapy.
| S-EPMC7727578 | biostudies-literature
Project description:Chimeric antigen receptor (CAR) T cells (CAR-T) have dramatically changed the treatment landscape of B-cell malignancies, providing a potential cure for relapsed/refractory patients. Long-term responses in patients with acute lymphoblastic leukemia and non Hodgkin lymphomas have encouraged further development in myeloma. In particular, B-cell maturation antigen (BCMA)-targeted CAR-T have established very promising results in heavily pre-treated patients. Moreover, CAR-T targeting other antigens (i.e., SLAMF7 and CD44v6) are currently under investigation. However, none of these current autologous therapies have been approved, and despite high overall response rates across studies, main issues such as long-term outcome, toxicities, treatment resistance, and management of complications limit as yet their widespread use. Here, we critically review the most important pre-clinical and clinical findings, recent advances in CAR-T against myeloma, as well as discoveries in the biology of a still incurable disease, that, all together, will further improve safety and efficacy in relapsed/refractory patients, urgently in need of novel treatment options.
| S-EPMC8327729 | biostudies-literature
Project description:Background: In recent years, chimeric antigen receptor-modified T (CAR-T) cell therapy for B-cell leukemia and lymphoma has shown high clinical efficacy. Similar CAR-T clinical trials have also been carried out in patients with refractory/relapsed multiple myeloma (RRMM). However, no systematic review has evaluated the efficacy and safety of CAR-T cell therapy in RRMM. The purpose of this study was to fill this literature gap. Methods: Eligible studies were searched in PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), CNKI, and WanFang from data inception to December 2019. For efficacy assessment, the overall response rate (ORR), minimal residual disease (MRD) negativity rate, strict complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) were calculated. The incidence of any grade cytokine release syndrome (CRS) and grade ≥3 adverse events (AEs) were calculated for safety analysis. The effect estimates were then pooled using an inverse variance method. Results: Overall, 27 studies involving 497 patients were included in this meta-analysis. The pooled ORR and MRD negativity rate were 89% (95% Cl: 83-94%) and 81% (95% Cl: 67-91%), respectively. The pooled sCR, CR, VGPR, and PR were 14% (95% Cl: 5-27%), 13% (95% Cl: 4-26%), 23% (95% Cl: 14-33%), and 15% (95% Cl: 10-21%), respectively. Subgroup analyses of ORR by age, proportion of previous autologous stem cell transplantation (ASCT), and target selection of CAR-T cells revealed that age ≤ 55 years (≤55 years vs. > 55 years, p = 0.0081), prior ASCT ≤70% (≤70% vs. > 70%, p = 0.035), and bispecific CAR-T cells (dual B-cell maturation antigen (BCMA)/BCMA + CD19 vs specific BCMA, p = 0.0329) associated with higher ORR in patients. Subgroup analyses of remission depth by target selection suggested that more patients achieved a better response than VGPR with dual BCMA/BCMA + CD19 CAR-T cells compared to specific BCMA targeting (p = 0.0061). In terms of safety, the pooled incidence of any grade and grade ≥ 3 CRS was 76% (95% CL: 63-87%) and 11% (95% CL: 6-17%). The most common grade ≥ 3 AEs were hematologic toxic effects. Conclusion: In heavily treated patients, CAR-T therapy associates with promising responses and tolerable AEs, as well as CRS in RRMM. However, additional information regarding the durability of CAR-T cell therapy, as well as further randomized controlled trials, is needed.
| S-EPMC7744881 | biostudies-literature
Project description:In this era of evidence-based medicine, significant progress has been made in the field of pharmacotherapeutics for the management of diabetic macular edema (DME). A. number of landmark clinical trials have provided strong evidence of the safety and efficacy of agents such as anti-vascular endothelial growth factors for the treatment of DME. Decades of clinical research, ranging from the early treatment of diabetic retinopathy study to the present-day randomized clinical trials (RCTs) testing novel agents, have shifted the goal of therapy from preventing vision loss to ensuring a maximum visual gain. Systematic study designs have provided robust data with an attempt to optimize the treatment regimens including the choice of the agent and timing of therapy. However, due to a number of challenges in the management of DME with approved agents, further studies are needed. For the purpose of this review, an extensive database search in English language was performed to identify prospective, RCTs testing pharmacological agents for DME. In order to acquaint the reader with the most relevant data from these clinical trials, this review focuses on pharmacological agents that are currently approved or have widespread applications in the management of DME. An update on clinical trials presently underway for DME has also been provided.
| S-EPMC4759901 | biostudies-other
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