Cilta-cel salvages ide-cel failure in relapsed multiple myeloma by driving distinct immune responses

ABSTRACT Ide-cel and cilta-cel are the two FDA-approved anti-BCMA CAR T cell therapies for the treatment of relapsed/refractory multiple myeloma. Here, we studied a patient who was initially treated with ide-cel with progressive disease and subsequently treated with cilta-cel with a complete response. To elucidate the underlying mechanisms underpinning the distinct clinical outcomes, we conducted multimodal, cross-tissue, and longitudinal single-cell analyses. This enabled us to directly compare the specific cellular and molecular factors distinguishing these two CAR therapies including their cell phenotypes, post-infusion kinetics, and endogenous immune landscapes. We found that the ide-cel infusion product was dominated by CD4+ CAR T cells, upregulated a terminal effector phenotype, and exhibited elevated activation signatures. Post-infusion, ide-cel CAR T cells failed to proliferate, sustain cytotoxicity, or migrate into the bone marrow, resulting in persistent myeloma cells and dysregulated monocytes and natural killer cells. In contrast, the cilta-cel infusion product exhibited a balanced ratio of CD4+ and CD8+ CAR T cells, upregulated a resident memory-like signature, and displayed signatures of IL-1 and IL-2 family cytokine signaling. Post-infusion, cilta-cel CAR T cells retained their resident memory-like profile, were durably retained in the peripheral blood, and successfully infiltrated the bone marrow, leading to effective tumor clearance and reestablishment of immune homeostasis. Our results present important clinical evidence that cilta-cel can serve as an effective salvage treatment following ide-cel failure. By providing a direct patient-matched comparison between two CAR therapies, our study uncovers important insights into both CAR T-cell intrinsic properties and immune environmental factors that contribute to effective BCMA CAR T-cell treatment. Competing Interest Statement P.A.R. reports research support/funding: BMS, Kite Pharma, Inc./Gilead, MorphoSys, Calibr, Tessa Therapeutics, Fate Therapeutics, Xencor, and Novartis Pharmaceuticals Corporation. Speaker's Bureau: Kite Pharma, Inc./Gilead; consultancy on advisory boards: AbbVie, Novartis Pharmaceuticals Corporation, BMS, Janssen, BeiGene, Karyopharm Therapeutics Inc., Takeda Pharmaceutical Company, Kite Pharma, Inc./Gilead, Sana Biotechnology, Nektar Therapeutics, Nurix Therapeutics, Intellia Therapeutics, and Bayer. Honoraria: Novartis Pharmaceuticals Corporation. B.D. reports research support/funding: GSK and Amgen; consultancy fees for Johnson and Johnson, Sanofi, COTA, and Canopy; independent review of a clinical trial for BMS. No disclosures were reported by the other authors. Funding Statement This work was supported by the NIH R21AI169159 grant and American Cancer Society Scholar Award (SG-22-136-01-1BCD) (to J.H.). T.P. was supported by the University of Chicago CSTR training grant (T32HL007381). Y.H. was supported by the University of Chicago MSTP Training Grant (T32GM007281). N.A. was supported by the University of Chicago MTCR training grant (T32CA009594). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was given ethical approval by the institutional review board at the University of Chicago Medicine (IRB number 18-0025). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors