Ultrasensitive BCMA CARs Deliver Responses With Tolerable Safety in R/R Multiple Myeloma

The use of the BCMA-directed CAR T-cell therapy D8 Fab CAR and the dual-targeting AUTO8 CAR T-cell therapy is safe and feasible in patients with relapsed/refractory multiple myeloma, according to early findings from the ongoing phase 1 MCARTY trial (NCT04795882) that were presented during the 2023 ASH Annual Meeting.¹

At a median follow-up of 6 months, the objective response rate (ORR) was 100% in a group of 11 patients who underwent infusion. Three patients had a partial response, 1 a very good partial response, and 7 had a complete response or stringent complete response. Overall, progression-free survival was not reached. Moreover, investigators reported no cases of immune effector cell-associated neurotoxicity (ICAN) syndrome.

Investigators aimed to develop an ultra-sensitive B-cell maturation antigen (BCMA) CAR that co-targets CD19 while using a CAR, as well as test the product in a clinical study.

“MCARTY is a recruiting phase 1 trial for relapsed/refractory multiple myeloma in 2 separate, parallel cohorts for direct comparison,” lead study author Lydia Lee, MD, clinical senior research fellow, University College London, said during the presentation.

Part 1 of the study was used to identify highly sensitive BCMA binders that were generated from a rat library. Binders were selected by phage display and next-generation sequencing, Lee noted, with pan-sequences transduced into human cells for further analyses. A total of 13 cells were identified, with a focus on ultra-low BCMA cell lines. Through this, the D8 binder was selected.

D8 was found to have increased BCMA binding with an increased surfaced CAR antigen which promoted greater sensitivity. Lee also highlighted an increase in efficacy on functional evaluation with the D8 Fab CAR construct.

When low-density antigens were presented compared with bb2121 and LCAR-B38M, there was an increased sensitivity to the former with D8 Fab CAR. Lee also indicated that bb2121 and LCAR-B38M are the basis for idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti), respectively. The in-vitro assays were observed to have superior kill with a 1:8 ratio to the BCMA low targets and a lack of proliferation at 96 hours in the absence of an antigen. This may be from a lack of tonic signaling compared with other BCMA CARs and assays.

Part 2 focused on co-targeting CD19 with obecabtagene autoleucel (obe-cel), which is a low-affinity binder. Obe-cel has shown to be persistent and tolerable, which is why it was selected as a co-targeting strategy for multiple myeloma.

Lee explained co-transduction was used as it does not disrupt obe-cel or D8 Fab CAR expression. Additionally, it shows several potential co-targeting strategies and leaves CARs intact. T cells were activated and transduced with the D8 viral effector alone or simultaneously with 2 separate antiviral constructs on the Prodigy automated platform.

The dual transduced T cell, AUTO8, contains 3 populations of CAR T cells that are single and dual expressing. This T cell can target both CD19 and BCMA.

Part 3 contained the MCARTY trial which was designed to test both D8 BCMA CAR and AUTO8, separating patients into 2 cohorts. A total of 13 patients were screened, 12 received treatment, and 1 had progressive disease. A total of 11 patients were infused. The median vein-to-vein time was 55 days.

Patients were screened, had CAR T cells extracted, and then were selected based on the Prodigy automated system with a protocol that lasted between 6 to 8 days. Three subsequent doses of cytophosphamide were given at 300 mg/m², and fludarabine at 30 mg/m² on days –5, –4, and –3. Patients then proceeded to CAR infusion with follow-up.

The trial design was a roll 6 design that was staggered. In cohort 1, BCMA CAR T cells were given at 50 x 10⁶. In cohort 2, they were given 50 x 10⁶ and 150 x 10⁶ to give a direct comparison.

Patients were enrolled on the trial if they had relapsed/refractory multiple myeloma, secretory disease, were triple exposed to prior treatment, were refractory to the last line of therapy, and had an ECOG performance status of 0 or 1. No selection based on BCMA expression.

The primary end points were safety and feasibility with secondary end points being response, survival, and CAR persistence.

In total, 82% of patients were male, and the median patient age was 50. Patients underwent a median of 4 prior lines of therapy. No patients had extramedullary disease, and only 1 patient had previous BCMA exposure.

Safety was comparable across the D8 BCMA CAR and AUTO8 cohorts at both the 50 x 10⁶ and 150 x 10⁶ dosing regimens. Overall, 91% of patients had cytokine release syndrome with a median time to onset of 0.5 days that lasted a median duration of 4 days. There were no reports of ICANs. Tocilizumab was administered to 64% of patients and 18% received steroids.

Reference

Lee LSH, Lim WC, Mactier C, et al. Development of a phase 1 study evaluating the activity of modular CAR T for multiple myeloma (MCARTY) targeting BCMA and CD19 for improved persistence. Blood, 2023;142(suppl 1):350. doi:10.1182/blood-2023-185085