Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma

Abstract

Background: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy showed remarkable efficacy in patients with relapsed or refractory multiple myeloma (RRMM). This phase 1 dose-escalation and expansion study developed C-CAR088, a novel second-generation humanized anti-BCMA CAR T-cell therapy, and assessed the safety and efficacy of three dosages of C-CAR088 in patients with RRMM.

Methods: Patients received lymphodepletion with three doses of cyclophosphamide (300 mg/m²) and three doses of fludarabine (30 mg/m²) on days -5, -4, and -3, followed by an infusion of C-CAR088 on day 0. Doses of 1.0×10⁶, 3.0×10⁶, and 6.0×10⁶ CAR T cells/kg (±20%) were tested in the dose-escalation cohorts and expansion cohorts. The primary endpoint was treatment safety, including the rate of treatment-emergent adverse events after cell infusion. Secondary endpoints were the overall response rate and progression-free survival. The exploratory endpoints were the quantification of C-CAR088 CAR T cells, selection of cytokines and chemokines in blood, and measurement of tumor BCMA expression.

Results: As of July 2, 2021, 31 patients had been infused with C-CAR088. Any grade cytokine release syndrome (CRS) occurred in 29 patients (93.5%), and grade 3 CRS occurred in 3 patients (9.7%). One patient from the high-dose group (4.5-6.0×10⁶ CAR T cells/kg) developed grade 1 neurotoxicity. No dose-limiting toxicities were observed in any dose group, and all adverse events were reversible after proper management. The overall response, stringent complete response, complete response (CR), and very good partial response rates were 96.4%, 46.4%, 10.7%, and 32.1%, respectively. The CR rate in the medium-dose (3.0×10⁶ CAR T cells/kg) and high-dose (4.5-6.0×10⁶ CAR T cells/kg) groups was 54.5% and 71.4%, respectively. In the CR group, 15 (93.7%) patients achieved minimal residual disease (MRD) negativity (test sensitivity >1/10^-5). All seven patients with double-hit or triple-hit multiple myeloma achieved MRD-negative CR.

Conclusions: The present study demonstrated that C-CAR088 had a good safety profile and high antitumor activity in patients with RRMM, constituting a promising treatment option for RRMM.

Trial registration number: NCT03815383, NCT03751293, NCT04295018, and NCT04322292.

Keywords: Antibodies, Neoplasm; Costimulatory and Inhibitory T-Cell Receptors; Hematologic Neoplasms.

Figure 1

Trial contents and curative effect. (A) Schematic diagram of C-CAR088 CAR, a second-generation anti-BCMA CAR. The scFv of C-CAR088 is derived from a human IgG1 antibody targeting the BCMA extracellular domain. (B) Flowchart of this trial. *Died of progressive disease before C-CAR088. #Died of septic shock on day 3 after C-CAR088. (C) Best overall response at each dose level. BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; CR, complete response; ORR, overall response rate; PD, disease progression; PR, partial response; scFv, single-chain variable fragment; SD, stable disease; VGPR, very good partial response.

Figure 2

Evaluation index. (A) Progression-free survival in the treatment groups. (B) Overall survival in the medium-dose and high-dose groups. (C) Duration of response in the medium-dose and high-dose groups. (D) Effect of baseline characteristics on CR and sCR to C-CAR088 T-cell therapy. BM, bone marrow; BCMA, B-cell maturation antigen; CR, complete response; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; MM, multiple myeloma; R-ISS, Revised International Staging System; sCR, stringent CR; UK, unknown.

Figure 3

Pharmacokinetics of CAR T cells and changes after C-CAR088 infusion. (A) Number of CAR copies at serial time points up to the most recent visit at the cut-off date; (B) C_max of CAR T-cell levels; (C) Area under the curve of CAR T-cell levels; (D) T_last of CAR T-cell levels; (E) T_max of CAR T-cell levels. (F) Changes in the levels of M-protein or serum-free light chain in the blood/urine of patients; (G) Changes in the serum levels of IL-6 and IFN-γ in the first month after C-CAR088 CAR T-cell infusion. The horizontal line within each box is the median. The lower and upper limits of each box represent the 25th and the 75th percentiles, respectively, and the error bars are 95% CIs. AUC0-28 days, area under the receiver operating characteristic curve; CAR, chimeric antigen receptor; Cmax, maximum transgene level; CRS, cytokine release syndrome; gDNA, genomic DNA; IFN, interferon; IL, interleukin; Tlast, time of last measurable transgene level; Tmax, time to reach Cmax.