Hypersensitive BCMA CARs provide responses with acceptable safety in R/R multiple myeloma

The use of BCMA-targeted CAR T-cell therapy D8 Fab CAR and dual-targeted 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), which were presented at 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 undergoing infusion. Three patients had a partial response, 1 a very good partial response, and 7 had a complete response or strict complete response. Overall, progression-free survival was not achieved. In addition, the investigators reported no cases of immune effector cell-associated neurotoxicity (ICAN) syndrome.

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

“MCARTY is a phase 1 study of relapsed/refractory multiple myeloma in 2 separate, parallel, head-to-head comparison cohorts,” lead study author Lydia Lee, MD, clinical senior 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. The 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 an emphasis on ultralow BCMA cell lines. By this the binder D8 was selected.

D8 was found to have increased binding of BCMA with increased CAR antigen on the surface, promoting greater sensitivity. Lee also highlighted an increase in efficacy in functional assessment with the D8 Fab CAR construct.

When low-density antigens were presented compared to bb2121 and LCAR-B38M, there was increased sensitivity to the former with the D8 Fab CAR. Lee also pointed out that bb2121 and LCAR-B38M are the basis for idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti), respectively. In-vitro assays were observed to have superior killing of 1:8 to low BCMA targets and no proliferation at 96 hours in the absence of antigen. This may be due to a lack of tonic signaling compared with other BCMA CARs and assays.

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

Lee explained that cotransduction was used because it did not disrupt obe-cel or D8 Fab CAR expression. Furthermore, it shows several potential co-targeting strategies and leaves CAR intact. T cells were activated and transduced with 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 CD19 and BCMA.

Part 3 contains the MCARTY study, which was designed to test both D8 BCMA CAR and AUTO8, dividing 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 average time from vein to vein is 55 days.

Patients were screened, CAR T cells were retrieved, and then selected based on the automated Prodigy system with a protocol that lasted between 6 to 8 days. Three consecutive doses of cytophosphamide at 300 mg/m2 were given2and fludarabine at 30 mg/m22 on days –5, –4 and –3. Patients were then switched to CAR infusion with follow-up.

The trial design was a roll 6 design that was displaced. 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 included in the trial if they had relapsed/refractory multiple myeloma, secretory disease, were triple-exposed to prior treatment, were refractory to last-line therapy, and had an ECOG efficacy status of 0 or 1. There was no selection on basis of BCMA expression.

The primary endpoints were safety and feasibility, with secondary endpoints being response, survival and resistance to CAR.

A total of 82% of the patients were male and the average age of the patients was 50 years. Patients had received a median of 4 prior lines of therapy. There were no patients with extramedullary disease and only 1 patient had previous exposure to BCMA.

Safety was comparable in the D8 BCMA CAR and AUTO8 cohorts and at 50 x 106 and 150 x 106 dosing regimens. Overall, 91% of patients experienced cytokine release syndrome with a median time to onset of 0.5 days, which lasted a median duration of 4 days. There are no messages about ICAN. 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 resistance. blood, 2023; 142 (Suppl. 1): 350. doi:10.1182/blood-2023-185085

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