BackgroundChimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM).MethodsThis ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m2. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 106 cells/kg [range, 0.07 to 2.1 × 106]) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group.ResultsAt data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade ≥ 3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval [CI], 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1 month (range, 0.4 to 3.5). At a median follow-up of 8 months, median progression-free survival was 15 months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached.ConclusionsLCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM.Trial registrationClinicalTrials.gov, NCT03090659; Registered on March 27, 2017, retrospectively registeredElectronic supplementary materialThe online version of this article (10.1186/s13045-018-0681-6) contains supplementary material, which is available to authorized users.

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LBA3001 Background: Chimeric antigen receptor engineered T cell (CAR-T) is a novel immunotherapeutic approach for cancer treatment and has been clinically validated in the treatment of acute lymphoblastic leukemia (ALL). Here we report an encouraging breakthrough of treating multiple myeloma (MM) using a CAR-T designated LCAR-B38M CAR-T, which targets principally BCMA. Methods: A single arm clinical trial was conducted to assess safety and efficacy of this approach. A total of 19 patients with refractory/relapsed multiple myeloma were included in the trial. The median number of infused cells was 4.7 (0.6 ~ 7.0) × 10e6/ kg. The median follow-up times was 208 (62 ~ 321) days. Results: Among the 19 patients who completed the infusion, 7 patients were monitored for a period of more than 6 months. Six out of the 7 achieved complete remission (CR) and minimal residual disease (MRD)-negative status. The 12 patients who were followed up for less than 6 months met near CR criteria of modified EBMT criteria for various degrees of positive immunofixation. All these effects were observed with a progressive decrease of M-protein and thus expected to eventually meet CR criteria. In the most recent follow-up examination, all 18 survived patients were determined to be free of myeloma-related biochemical and hematologic abnormalities. One of the most common adverse event of CAR-T therapy is acute cytokine release syndrome (CRS). This was observed in 14 (74%) patients who received treatment. Among these 14 patients there were 9 cases of grade 1, 2 cases of grade 2, 1 case of grade 3, and 1 case of grade 4 patient who recovered after treatments. Conclusions: A 100% objective response rate (ORR) to LCAR-B38M CAR-T cells was observed in refractory/relapsed myeloma patients. 18 out of 19 (95%) patients reached CR or near CR status without a single event of relapse in a median follow-up of 6 months. The majority (14) of the patients experienced mild or manageable CRS, and the rest (5) were even free of diagnosable CRS. Based on the encouraging safety and efficacy outcomes, we believe that our LCAR-B38M CAR-T cell therapy is an innovative and highly effective treatment for multiple myeloma.

Background LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. Methods LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 × 106 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. Results As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade ≥ 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. Conclusions The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285.

Background: In RRMM, the median overall survival (OS) of pts with RRMM who progressed after exposure to ≥3 prior therapies is ~13 mo, indicating a high unmet need. LCAR-B38M is a structurally differentiated CAR-T cell therapy containing a 4-1BB co-stimulatory domain and 2 BCMA-targeting single-domain antibodies designed to confer avidity. Earlier results from LEGEND-2 (NCT03090659), a first-in-human phase 1 study using LCAR-B38M CAR-T cells in 74 pts with RRMM conducted in 4 hospitals in China (Jiangsu Provincial People's Hospital; Ruijin Hospital; Changzheng Hospital; and the Second Affiliated Hospital of Xi'an Jiaotong University), showed encouraging efficacy and manageable safety. Key eligibility criteria included RRMM with ≥3 prior lines of therapy. Here, we present long-term follow-up data on safety and efficacy from the Xi'an site. Methods: In the Xi'an site-specific protocol (n=57), lymphodepletion was performed using cyclophosphamide (Cy; 300 mg/m2)alone for 3 days. LCAR-B38M (median CAR+ T cells, 0.5×106 cells/kg; range, 0.07-2.1 × 106) was infused in 3 split infusions. The primary objective was to evaluate the safety of LCAR-B38M; the secondary objective was to evaluate anti-myeloma response of treatment. Adverse events (AEs) were graded using the NCI-CTCAE v4.03, cytokine release syndrome (CRS) was assessed per Lee et al. 2014, and response was evaluated using IMWG criteria. Results: As of the 12/31/18 cutoff date (median follow-up, 19 mo; 95% confidence interval [CI], 17-22), enrollment at Xi'an is complete, and 57 pts have been infused with LCAR-B38M. AEs were reported by all pts: pyrexia (91%), CRS (90%), thrombocytopenia (49%), and leukopenia (47%). Grade ≥3 AEs were reported by 65% of pts: leukopenia (30%), thrombocytopenia (23%), and increased aspartate aminotransferase (21%). CRS was mostly grade 1 (47%) and 2 (35%); 4 pts (7%) had grade 3 events; no grade 4/5 CRS was observed. Neurotoxicity was observed in 1 pt (grade 1 aphasia, agitation, seizure-like activity). The median time to onset of CRS was 9 days (range, 1-19) with a median duration of 9 days (range, 3-57); all but 1 CRS events resolved. Peak levels of LCAR-B38M (≥1x104 copies/µg genomic DNA) were observed in a majority of pts with blood samples for analysis (n=32). LCAR-B38M was not detectable in peripheral blood in 71% of pts at 4 mo; 5 pts showed CAR-T cell persistence for up to 10 months. The overall response rate (partial response [PR] or better) was 88% (95% CI, 76-95), complete response (CR) was achieved by 42 pts (74%; 60-85), very good partial response (VGPR) by 2 pts (4%; 0.4-12), and PR by 6 pts (11%; 4-22). Of pts with CR, 39/42 were minimal residual disease negative (MRD-neg, 8-color flow cytometry). The median time to first response was 1.2 mo. There was no relationship between best response and baseline BCMA expression level or weight-adjusted CAR+ cells infused (Fig 1a,b). At cutoff, the median follow-up was 19 mo [17-22]. Median OS has not yet been reached. The OS rate at 18 mo was 68% (54─79) with a median duration of response (mDOR) of 22 mo (13-29). Of MRD-neg pts with CR, 91% (75-97) are still alive at data cut, with a 27 mo (16-NE) mDOR. Overall, 26 (46%) of 57 all-treated pts and 25 (64%) of 39 MRD-neg pts with CR remain progression-free. The median progression-free survival (PFS) for all-treated pts was 20 mo (10-28); median PFS for MRD-neg pts with CR was 28 mo (20-31). At 18 months, the PFS rate was 50% (36-63) for all pts and 71% (52-84) for MRD-neg pts with CR. Factors contributing to long-term response are shown in Fig 1c,d. Seventeen pts died during the study and the follow-up period: progressive disease (PD; n=11), disease relapse, PD + lung infection, suicide after PD, esophageal carcinoma, infection, and pulmonary embolism and acute coronary syndrome (n=1 each). Of these, 4 did not achieve PR or better; 1 was not evaluable. Conclusions: This study provides evidence that LCAR-B38M is a highly effective therapy for RRMM, regardless of baseline BCMA expression. LCAR-B38M displayed a manageable safety profile consistent with its known mechanism of action and, with a median follow-up of 19 months, demonstrated deep and durable responses in pts with RRMM. A phase 1b/2 clinical study is ongoing in the United States (CARTITUDE-1, NCT03548207, JNJ-68284528), and a phase 2 confirmatory study has initiated in China (CARTIFAN-1, NCT03758417). Figure 1 Disclosures Zhuang: Nanjing Legend Biotech: Employment. Fan:Legend Biotech: Employment, Equity Ownership.