bb21217

P1, N=72, Completed, 2seventy bio | Active, not recruiting --> Completed | Trial completion date: Oct 2025 --> Dec 2022 | Trial primary completion date: Oct 2025 --> Dec 2022

Introduction: Idecabtagene vicleucel (ide-cel, bb2121) is the first chimeric antigen receptor (CAR) T cell therapy approved for the treatment of relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody...Patients underwent lymphodepletion with fludarabine (30 mg/m 2 ) and cyclophosphamide (300 mg/m 2 ) daily for 3 days, then received a single infusion of bb21217 at 150, 300 or 450 x 10 6 CAR+ T cells...Median time to first onset of CRS was 2 days (1-20); tocilizumab (38 pts) + corticosteroids (12 pts) was used to manage CRS... Adverse events are consistent with known toxicities of CAR T cell therapies. Efficacy results are encouraging with a median DOR estimate of 17M, CR rate continues to mature. Patients with higher levels of proliferative, less differentiated memory like CAR+ T cells at peak expansion are more likely to experience prolonged DOR, continuing to support the hypothesis that the memory like T cell phenotype associated with bb21217 results in prolonged DOR.

Other Constructs of Interest Orva-cel (orvacabtagene autoleucel) is an anti-BCMA CAR T product with a construct containing a fully human scFv, an optimized spacer, a 4-1BB co-stimulatory domain, and a CD3z activation domain...Bb21217 has an identical construct to ide-cel except for coculturing with the phosphoinositide 3 kinase inhibitor (PI3K) bb007 during ex vivo culture to enrich for T cells displaying a memory-like phenotype...The ORR was 94%.17 P-BCMA-101 is a novel construct using an anti-BCMA Centyrin™ fused to a 4-1BB costimulatory domain and CD3z signaling domain...Both ide-cel and cilta-cel are being evaluated in various patient populations, including early-relapse and newly diagnosed high-risk patients...The first results of an allogeneic BCMA-directed CAR-T was with ALLO-715. The initial results from the UNIVERSAL phase 1 study in RRMM are encouraging, with responses reported and more attenuated toxicity.26 Others, including CTX120, BCMAUCART, UCART CS1, and PBCAR269A, are in development and in early-phase studies...Despite these impressive results, however, patients with MM continue to relapse. Moving these therapies earlier in the course of the disease, continued refinement of next-generation products, and rational combination strategies that may defer or prevent relapse should continue to improve on these results with the goal of finally reaching that elusive cure.

bb21217, a next-generation BCMA CAR T cell therapy contains the same CAR construct as ide-cel, but uses ex vivo culture in the presence of a PI3-kinase inhibitor to enrich the final product with memory-like T cells. T cell engaging bispecific antibodies, while not a cellular therapy, offer another approach to driving T cell mediated BCMA-targeted tumor killing. Taken together these data support the benefit of BCMA targeted, T cell activating immunotherapies for the treatment of advanced myeloma.

bb21217 is a BCMA-directed chimeric antigen receptor (CAR) T cell therapy that uses the same CAR molecule as idecabtagene vicleucel (ide-cel, bb2121), but adds the PI3K inhibitor bb007 during manufacturing to enrich the drug product (DP) for memory-like T cells, thereby reducing the proportion of highly differentiated or senescent T cells. As seen with other CAR T cell studies, the quality of incoming PBMCs, in particular the fraction of T cells with a late differentiation/senescent phenotype, influences initial and sustained clinical response. The analyses reported here support the mechanistic hypothesis of bb21217, suggesting the presence of early memory like T cells in PBMC and/or DP may contribute to high peak expansion and prolonged DOR, while presence of highly differentiated or senescent T cells may negatively impact these measures. Further clinical evaluation of bb21217 and robust correlative analyses will be important to help contextualize the influence of patient and product characteristics on clinical outcomes.

bb21217 is an anti-BCMA CAR T cell therapy that uses the same CAR molecule as idecabtagene vicleucel (bb2121), but adds the PI3K inhibitor bb007 during ex vivo culture to enrich the drug product (DP) for memory-like T cells, thereby reducing the proportion of highly differentiated or senescent T cells...Patients undergo lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days, then receive a single infusion of bb21217 at 150, 300 or 450 x 106 CAR+ T cells...Median time to first onset was 3 days (1-20); tocilizumab (18 pts) +/- corticosteroids (6 pts) was used to manage CRS... The adverse events observed are consistent with known toxicities of CAR T cell therapies. Initial efficacy results with bb21217 are encouraging, with 48% of patients treated across target dose levels of 150-450 obtaining ≥VGPR. The presence of T cell markers associated with memory and the absence of T cells markers associated with differentiation/senescence in DP correlated positively with peak expansion and DOR.