Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma

Abstract

Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.

B cell maturation antigen‐specific chimeric antigen receptor T cells for relapsed or refractory multiple myeloma: A meta‐analysis

“…The baseline characteristics of the included studies are listed in Table 1. A total of 314 patients were included in the 18 studies, [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] all of which were single-arm early phase studies that included only patients with RRMM (17 studies) or newly diagnosed myeloma (1 study). Patients included in RRMM studies were heavily pretreated and received a median of 6 prior lines of treatment (proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, 1-2 autologous stem cell transplants).…”

“…31,43 Two studies did not report on the costimulatory domain that was used for the CAR T product. 32,36 Most studies used fludarabine and cyclophosphamide for lymphodepletion while one study used busulfan and cyclophosphamide 46 and one study used cyclophosphamide only. 42 Most studies included patients who underwent autologous stem cell transplantation as part of prior treatment while transplant data were lacking in six studies.…”

“…Additionally, the risk of evidence imprecision F I G U R E 1 shows the PRISMA flow diagram of the study selection process. Out of 18 identified studies, [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48] three were included only in the qualitative review because they evaluated CAR T products that, in addition to BCMA, targeted other antigens such as CD19 and CD38. [46][47][48] The remaining 15 studies were included in the quantitative systematic review and meta-analysis [Colour figure can be viewed at wileyonlinelibrary.com]…”

“…Fifteen studies and 285 patients with RRMM were included in the pooled analysis of efficacy and safety of anti-BCMA CAR T cells. [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] The pooled proportion of overall response was 82% with a 95% confidence interval (CI) of 74%-88% (I 2 = 44%; Figure 2A). This was pooled from all 15 studies involving 264 evaluable patients of whom 219 showed a response lasting a median of 10 months.…”

Development of CAR-T Cell Therapy for B-ALL Using a Point-of-Care Approach

“…Based on these results, anti-CD19 CAR-T cells were recently approved by the FDA and European Commission for use in USA and Europe, consisting in a new treatment option for patients with B cell malignancies. Similar therapies targeting antigens like CD22 (6,7), BCMA (8)(9)(10) and EGFRvIII (11) are currently being evaluated in clinical trials, which will further extend the clinical application of CAR-T cell therapy to other types of cancer and potentially improve the response rates in the diseases already approached by CAR-T cell therapies.…”