Molecular and Phenotypic Profiling of Drug Product and Post-Infusion Samples from CRB-402, an Ongoing: Phase I Clinical Study of bb21217 a BCMA-Directed CAR T Cell Therapy

Introduction: B-cell maturation antigen (BCMA) is primarily expressed by malignant and normal plasma cells, making it an attractive target for the treatment of multiple myeloma (MM). 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. We conducted correlative analyses to investigate the mechanistic hypothesis that CAR+ T cells with memory like phenotypes may persist and function longer, which may be one determinant of duration of response (DOR). Methods: An ongoing phase I clinical study (CRB-402; NCT03274219) is assessing safety and efficacy of bb21217 in relapsed/refractory MM patients. A total of 44 patients had PBMCs, collected from apheresis, and DP characterized by RNA sequencing (RNAseq) and mass Cytometry (CyTOF). The correlation of T cell phenotype with peak expansion, response and DOR per IMWG Uniform Response Criteria was explored. P-values were determined by Wilcoxon test, Spearman correlation, or Cox PH regression on DOR with categorical marker values (high/low). Results: In this patient population, substantial cross patient heterogeneity in T cell phenotypes was observed both in PBMCs and DP. Late differentiation/senescent markers in PBMCs were negatively correlated with clinical response. In particular, patients whose DP had higher expression of CD57 had lower peak expansion (p2x105copies/ug), consistent with the CYTOF findings. Early activation markers (CD38 p Conclusion: 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. Disclosures Finney: bluebird bio: Current Employment, Current equity holder in publicly-traded company. Yeri:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Mao:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Pandya:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Alonzo:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Hopkins:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Hymson:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Hu:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Foos:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Bhadoriya:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Hintzen:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Gioia:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Timm:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Massaro:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Hause:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Kaiser:BMS: Current Employment, Current equity holder in publicly-traded company. Martin:BMS: Current Employment, Current equity holder in publicly-traded company. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Raje:Caribou: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Celgene: Consultancy; BMS: Consultancy; Immuneel: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Bluebird, Bio: Consultancy, Research Funding; Amgen: Consultancy. Berdeja:Novartis: Research Funding; Lilly: Research Funding; Legend: Consultancy; Takeda: Consultancy, Research Funding; Servier: Consultancy; Teva: Research Funding; Vivolux: Research Funding; Bluebird: Research Funding; Acetylon: Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Research Funding; BMS: Consultancy, Research Funding; Bioclinica: Consultancy; CRISPR Therapeutics: Consultancy, Research Funding; Constellation: Research Funding; Cellularity: Research Funding; Celgene: Consultancy, Research Funding; Glenmark: Research Funding; Genentech, Inc.: Research Funding; EMD Sorono: Research Funding; CURIS: Research Funding; Kite Pharma: Consultancy; Kesios: Research Funding; Karyopharm: Consultancy; Janssen: Consultancy, Research Funding; Prothena: Consultancy; Poseida: Research Funding. Grande:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Bitter:Novartis AG, Predicant Biosciences, Biospect, F Hofmann-La Roche: Ended employment in the past 24 months; bluebird bio: Current Employment, Current equity holder in publicly-traded company; Novartis: Ended employment in the past 24 months, Patents & Royalties. Petrocca:bluebird, bio: Current Employment, Current equity holder in publicly-traded company. Friedman:bluebird bio: Current Employment, Current equity holder in publicly-traded company. Sangurdekar:bluebird bio: Current Employment, Current equity holder in publicly-traded company; Biogen: Ended employment in the past 24 months.