High interest in phase I study
A phase I study presented in Blood has attracted interest because the novel BCMA-targeting CAR agent (CT103A) being tested is fully human.4 In an accompanying editorial, Lee and Yong note that doubt for any real potential for durable CAR T therapy responses in multiple myeloma is raised by the poor persistence of multiple myeloma CAR T cells in multiple myeloma patients.3
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Multiple myeloma cells produce monoclonal proteins of varying types.
In the earliest trials of BCMA CARs, while reported rates of objective antimyeloma responses were in the approximately 33%-88% range among patients with relapsed/refractory multiple myeloma (RRMM), persistence was typically 6 months or less. Lee and Yong point out, however, that while correlation between persistence and duration of response (DOR) has been variable, median persistence was 308 days in the phase I study. Wang and colleagues, the phase I study authors, state that levels of CAR T-cell proliferation and duration of cellular persistence may be determinants of DOR in CAR T therapy for multiple myeloma. They observe that the multiple mechanisms potentially responsible for the inability of some CAR T cells to survive in vivo, may include antigen escape, T-cell intrinsic mechanisms, tumor microenvironment–mediated suppression, and host anti-CAR immunity. CARs with humanized or fully human single-chain variable fragments (scFvs), prior studies suggest, may retain antitumor activity through bypassing potential host anti-CAR immunogenicity.
In the study, CT103A, a fully human scFv, was tested in an open-label, single-arm design for safety and preliminary efficacy in 18 patients (8 female; median age 53.5 years) with RRMM (at least three lines of prior therapies including a proteasome inhibitor and an immunomodulatory agent) who had undergone leukapheresis and had received lymphodepletion chemotherapy with fludarabine and cyclophosphamide. Four patients (22.2%) had been treated previously with murine anti-BCMA CAR T cells. Safety and tolerability (including dose-limiting toxicity) were the primary endpoints, with efficacy and pharmacokinetics secondary.
Rapid responses
Two weeks after infusion, the overall response rate (ORR) was 77.8% (14 of 18) and by 1 month it was 88.9% (16 of 18). Eventually, all responded and 72.2% (13 of 18) achieved a complete response (CR) or stringent complete response (sCR). All 17 patients evaluated for minimum residual disease (MRD) in bone marrow were MRD-negative at 10-4 nucleated cells by flow cytometry within 1 month. Median DOR was 325 days (range, 7-573 days) for all patients and 412 days (range, 213-573 days) for the 13 with CR/sCR. CAR transgenes were detectable at the cutoff date in 77.8% of patients, with a median CAR transgene persistence of 307.5 days.
During follow-up, four deaths were reported, including one patient with persistent sCR (sudden severe infection). Progression-free survival (PFS) and overall survival (OS) rates at 1 year were 58.3% and 75%, respectively. Extramedullary myeloma was associated with a shortened PFS (79.1% versus 20.0%, P = .015), but not OS (79.1% versus 60.0%, P = .328) at 1 year.
All patients experienced grade 3 or higher adverse events, most of which were expected hematologic effects of lymphodepleting chemotherapy and CT103A infusions. Grade 1 and 2 cytokine release syndromes occurred in 70.6% patients (17 of 18), with 1 grade 4 event (5.9%). The patients receiving a dose of up to 3.0 × 106 CAR+ T cells/kg required less treatment of cytokine release syndrome than the patients who received a dose of 6.0 × 106 CAR+ T cells/kg. No immune effector cell–associated neurotoxicity syndrome was observed. Antidrug antibody positivity occurred in only 1 patient.
Two characteristics of CT103A may contribute to its long persistence, stated study senior author Jianfeng Zhou, MD, PhD, chairman and professor of the department of hematology, Tongji Hospital in Wuhan, China. “One is the reduced immunogenicity achieved by the fully human construct; another is the relatively low binding affinity of the CAR binder. Notably, four patients who previously received murine BCMA CAR were included and still benefit from CT103A. It demonstrates the possibility of retreatment with a different CAR.” Dr. Zhou also emphasized that the lack of ICANS in the entire cohort reflects the excellent safety profile of CT103A.
The editorial commentary in Blood by Lydia Sarah Hui Lee, MD, and Kwee L. Yong, PhD, underscored impressive responses to CT103A, specifically to the median time to response of 15 days, the 100% ORR, and the not reached median progression-free survival at 394 days).5 The best results in other published nonhuman BCMA CAR T-cell trials, they note, were about 1 month (time to response), approximately 33%-88% (ORR), and median progression-free survival of 7-15 months.
Immune responses, Dr. Yong said in an interview, can guide subsequent treatment. “For example, if a patient previously exposed to BCMA CAR T cells in which the construct is either chimeric or humanized, but retains some murine elements, and had detectable antimurine antibodies, we may aim for a fully human one if we are considering treating with a different BCMA CAR T-cell product.” She added, “On the other hand, a similar patient whose serum did not contain such antibodies may be a candidate for a humanized product that retained some murine elements.”
Wang and colleagues concluded, “Altogether, CT103A is safe and highly active in patients with relapsed/refractory multiple myeloma and can be developed as a promising therapy for relapsed/refractory multiple myeloma.”4 An ongoing multicenter phase II trial with single-arm design is recruiting 100 patients. The infusion dosage, suggested by the phase I trial, is 1 × 106 cells/kg. Endpoints include efficacy and safety.