A Phase 1/2 Study of a Novel Fully Human B-Cell Maturation Antigen-Specific CAR T Cells (CT103A) in Patients with Relapsed and/or Refractory Multiple Myeloma
Authors: Li Chunrui , Wang Di , Song Yongping , Li Jianyong , Huang He , Chen Bing , Liu Jing , Hu Kai , Ren Hanyun , Zhang Xi , Li Zhenyu , Zou Dehui , Yin Qingsong , Chen Lijuan , HU Yongxian , Xu Yong , Cheng Qian , Guo Yuelu , Dong Yujun , Gao Li , Xu Aining , Cai Songbai , Wang Wen , Wu Ming , Wang Jue , Chen Liting , Zhou Jianfeng , Qiu Lugui 
Published: November 2021

Abstract
Background： CT103A, a fully human BCMA-specific chimeric antigen receptor (CAR) T-cell therapy product showed excellent safety and promising efficacy in heavily pretreated relapsed and refractory multiple myeloma (RRMM) patients in our previous report [Blood. 2021; 137 (21): 2890-2901]. The unique CAR structure containing fully human single-chain variable fragments (scFvs) may bypass the potential host anti-CAR immunogenicity and retain antitumor activity. Here we reported the safety and efficacy results of 71 patients in 1.0×10 6 CAR+ T cells/kg cohort from the ongoing phase1/2 study (ChiCTR1800018137/ ChiCTR2000033946). Notably, it was the first time that prior BCMA CAR-T exposed patients were eligible to participate in an anti-BCMA CAR-T cell trial.
Methods： This phase 1/2 study of CT103A is single-arm designed and is conducted in 13 centers in China. The study enrolled RRMM patients who had received ≥ 3 lines of prior therapies containing at least a proteasome inhibitor and an immunomodulatory agent and were refractory to their last line of treatment. 1.0 × 10 6 CAR+ T cells/Kg was previously identified as recommended phase 2 dose (RP2D). Lymphodepletion with fludarabine and cyclophosphamide was performed for three consecutive days. After 1-day rest, patients received CT103A. The primary objectives of this study were to assess the safety and efficacy of CT103A at RP2D. The cellular pharmacokinetic profile of CT103A in peripheral blood was investigated by measuring CAR transgene levels using droplet digital polymerase chain reaction (ddPCR) and CAR-T cells by flow cytometry. Minimal residual disease (MRD) negativity was evaluated in bone marrow aspirate by standardized Euroflow 8-color flow cytometry with a minimum sensitivity of 10 -5 nucleated cells. Immunogenicity was assessed by MSD-based antidrug antibody (ADA) assay.
Results: As of the July 15, 2021, 71 patients [59.2% male; median age 58.0 years (range 41-71)] with RRMM received CT103A (9 in phase 1a; 17 in phase 1b; 45 in phase 2). The median follow-up time was 147 days (range 31 to 1029). The treated patients had received a median of 4 (range 3-13) lines of prior therapy. 28.2% and 18.3% were previously treated with auto-HSCT and anti-CD38 antibody respectively. Notably, 18.3% had previously received CAR-T therapy. What's more, 7% of the patients had the extramedullary disease at baseline, and 76.1% had high-risk cytogenetics.
The most common ≥ grade 3 treatment-related AEs were hematological toxicities. 93.0% of the patients experienced CRS, among which only 2.8% were grade 3. All CRS cases were rapidly relieved after conventional CRS intervention, including tocilizumab and steroids. The median time to CRS onset was 6 days (range 1-12) with a median duration of 4 days (range 1-27). Only one (1.4%) patient experienced grade 2 ICANS which manifested as a transiently decreased level of consciousness and soon recovered without intervention.
All 71 patients were evaluable for at least one month of efficacy assessment. The median time to first response was 15 days (range 11-124). A 94.4% ORR was observed, with 50.7% ≥ CR, 26.8% VGPR, and 16.9% PR. Among them, 50 patients who have completed follow-up of 3 months achieved 96.0% ORR, with 54.0% ≥ CR, 28% VGPR, and 14% PR. For 13 patients who have previously been treated with CAR-T therapy, ORR was 76.9%, with ≥ CR rate of 38.5%，VGPR of 15.4%, and PR of 23.1%. Of the 69 patients with evaluable bone marrow aspirate, 92.8% achieved MRD-negativity with a median time to MRD-negative of 17 days (range 13-180), and among them, 75.0% (95%CI 53.1-87.6%) achieved sustained MRD negativity over six months.
The expansion of CT103A reached the peak at a median of 12 days (range 5 to 29). CT103A was still detectable in 88.5% (23/26) patients at 6 months and 87.5% (14/16) patients at 12 months after infusion. The first enrolled patient remains in sCR for 34 months with significant persistence of CT103A transgene. In addition, only 2 of 71 patients were detected positive for anti-drug antibody, which was reported to be a high-risk factor for disease relapse/progression after CAR-T therapy.
Conclusion: The impressive efficacy of CT103A, including time to response, overall response rate, and durability, was corroborated by robust expansion and prolonged persistence of CT103A. The expansion and clinical benefits of CT103A did not seem to be influenced by prior murine BCMA CAR-T.

Disclosures
No relevant conflicts of interest to declare.