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. 2025 Aug 6;33(8):3576-3589.
doi: 10.1016/j.ymthe.2025.04.019. Epub 2025 Apr 18.

Enhanced CAR-T cell function and mitochondrial fitness from earlier unfractionated stem cell product in multiple myeloma

Ciara L Freeman  1 , Julieta Abraham-Miranda  2 , Meghan Menges  2 , Reginald M Atkins  2 , Jerald Noble  2 , Hien Liu  1 , Salvatore Corallo  2 , Luis A Cuadrado Delgado  2 , Albert J Ribickas  3 , Constanza Savid-Frontera  2 , Gabriel de Avila  2 , Omar A Castaneda Puglianini  1 , Jose Ochoa-Bayona  1 , Doris K Hansen  1 , Melissa Alsina  1 , Rachid Baz  4 , Taiga Nishihori  1 , Kenneth H Shain  4 , Frederick L Locke  5
Affiliations

Enhanced CAR-T cell function and mitochondrial fitness from earlier unfractionated stem cell product in multiple myeloma

Ciara L Freeman et al. Mol Ther. .

Abstract

Chimeric antigen receptor T (CAR-T) cells targeting B cell maturation antigen (BCMA) have changed the treatment landscape for patients with relapsed and refractory multiple myeloma. However, T cell dysfunction associated with progressive disease and multiple prior lines of therapy (PLOT) raises concerns about the feasibility of consistently manufacturing effective CAR-T cells. We investigated the practicality of utilizing previously cryopreserved mobilized apheresis to generate potent anti-BCMA CAR-T cells. Paired patient samples collected longitudinally from (1) mobilized, unfractionated apheresis obtained before hematopoietic cell transplantation (mobHCT) and (2) apheresis obtained for commercial CAR-T manufacture (aphCAR) were directly compared head to head. The median time from transplant to commercial CAR-T infusion was 4.2 years (range, 2.5-12.5 years), and before CAR-T collection all patients were triple-class exposed. Analysis revealed that mobHCT samples exhibited a higher CD4:CD8 ratio and a greater proportion of naive T cells (CCR7+CD45RO-) in both CD4 and CD8 compartments compared with aphCAR samples. CAR-T cells derived from mobHCT samples demonstrated superior expansion during manufacturing, enhanced interleukin-2 secretion, reduced expression of checkpoint inhibitors, improved cytotoxicity through multiple stimulation rounds, and enhanced mitochondrial function. These findings underscore the potential of utilizing cryopreserved mobilized apheresis collected earlier in the disease course to produce potent and metabolically robust CAR-T cells.

Keywords: BCMA; CAR-T cell therapy; apheresis; hematopoietic cell transplantation; metabolic fitness; multiple myeloma.

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Conflict of interest statement

Declaration of interests C.L.F. reports Honoraria/consulting BMS/Celgene, ONK therapeutics & Janssen and research funding from BMS and Janssen. J.A.M., M.M., R.M.A., J.N., and H.L. report a role with the speakers’ bureau for Sanofi. O.A.C.P. reports honoraria/consulting Legend Biotech USA. D.K.H. reports research funding from Bristol-Myers Squibb, Karyopharm, and Adaptive Biotech and consulting or advisory role for Bristol-Myers Squibb, Janssen, Pfizer, and Karyopharm. D.K.H. is also supported by the Pentecost Family Myeloma Research Center. M.A. reports consulting for Janssen, BMS, and Sanofi, and research support from BMS. R.B. reports honoraria/consulting for BMS, Janssen, and Pfizer and research funding from BMS, Janssen, Abbvie, Regeneron, and Karyopharm. T.N. reports clinical trial support (to the institution) by Novartis, clinical trial support (drug only supply to the institution) by Karyopharm, consultancy for ImmunoGen, and advisory board membership for Medexus. K.H.S. reports consultancy, advisor, and/or speaker roles with Adaptive Biotech, Janssen, BMS, Takeda, Sanofi, and Glaxo Smith Kline; research funding with Karyopharm and Abbvie; and funds from BMS, Amgen, and Janssen-funded clinical trials. F.L.L. reports scientific advisory role/consulting fees from A2, Allogene, Amgen, Bluebird Bio, BMS, Calibr, Caribou, Cowen, EcoR1, Gerson Lehrman Group (GLG), Iovance, Kite Pharma, Janssen, Legend Biotech, Novartis, Sana, Umoja, and Pfizer; data safety monitoring board membership for the NCI Safety Oversight CAR T cell Therapies Committee; research contracts/grants from Kite Pharma (Institutional), Allogene (Institutional), CERo Therapeutics (Institutional), Novartis (Institutional), BlueBird Bio (Institutional), 2SeventyBio (Institutional), BMS (Institutional), the National Cancer Institute (R01CA244328 MPI: Locke; P30CA076292 PI: Cleveland), the Leukemia and Lymphoma Society Scholar in Clinical Research (PI: Locke); patents, royalties, other intellectual property for several patents held by the institution in my name (unlicensed) in the field of cellular immunotherapy; and education or editorial activity for Aptitude Health, ASH, BioPharma Communications CARE Education, Clinical Care Options Oncology, Imedex, and the Society for Immunotherapy of Cancer.

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