Development of a Fully Non-Viral 1XX-enhanced BCMA CAR-T Cell Therapy for Multiple Myeloma
) locus, 1XX CAR signaling architecture to enhance potency and durability, and non-viral manufacturing with a single-stranded DNA repair template to improve efficiency and yield. This approach confers physiological CAR expression, reduces insertional mutagenesis, and improves persistence by mitigating tonic signaling and exhaustion. Our GMP manufacturing process consistently achieved high CAR integration (37.7-72.7%) and yields across all full-scale runs and met predefined release criteria for identity, purity, safety, and quality. In NSG mouse models of MM, the UCCT-BCMA-1 product exhibited exceptionally potent tumor control, CAR-T cell expansion 100-1000-fold greater than that of lentiviral constructs, and durable clearance of myeloma cells after multiple rechallenges. These findings establish a CRISPR-edited, fully non-viral manufacturing platform for next-generation 1XX-BCMA CAR-T therapies with enhanced persistence, safety, and efficacy. One Sentence Summary: -targeted 1XX-BCMA CAR-T therapy with improved safety, potency, and persistence in relapsed and refractory multiple myeloma.
Authors
- Luis A. Acevedo
- Moloud Ahmadi (ORCID: https://orcid.org/0000-0002-6372-8934)
- Derrick Houser
- Chang Liu (ORCID: https://orcid.org/0009-0003-1294-9686)
- Joseph J. Muldoon (ORCID: https://orcid.org/0000-0003-3784-3565)
- Brianna Liang
- Petros Giannikopoulos (ORCID: https://orcid.org/0000-0003-4342-1756)
- Justin Eyquem (ORCID: https://orcid.org/0000-0001-8262-1190)
- Dehui Kong (ORCID: https://orcid.org/0000-0001-7722-7172)
- Jae Hyun J. Lee
- Niran Almudhfar
- Brian R. Shy (ORCID: https://orcid.org/0000-0001-9569-3708)
- Alvin Ha (ORCID: https://orcid.org/0000-0002-7092-9072)
- Alexis Talbot (ORCID: https://orcid.org/0000-0001-6734-413X)
- Vincent Allain (ORCID: https://orcid.org/0000-0002-1068-7892)
- Kevin Briseno
- Jing-Yi J. Chung
- Sreenivasan Paruthiyil (ORCID: https://orcid.org/0009-0006-3736-7684)
- Ayal Hendel (ORCID: https://orcid.org/0000-0002-3388-6202)
- Yasaman Mortazavi
- Serena S. Kwek (ORCID: https://orcid.org/0000-0001-5097-2711)
- Nechama Kalter (ORCID: https://orcid.org/0000-0001-7952-4963)
- K Li
- Zhongxia Qi (ORCID: https://orcid.org/0000-0001-7190-6457)
- Michel Sadelain
- Shanshan Lang
- Yongchang Ji
- Isabelle Rivière
- David Y. Oh
- Alexander Marson
- Michael Rosenberg
- Thomas Martin
- Charlotte Wang
- Zhongmei Li
- William Nyberg
- Netravathi Krishnappa
Institutions
- Gladstone Institutes (US)
- Bar-Ilan University (IL)
- Inserm (FR)
- University of California, San Francisco (US)
- Université Paris Cité (FR)
- Innovative Genomics Institute (US)
- Parker Institute for Cancer Immunotherapy (US)
- Thermo Fisher Scientific (United States) (US)
- Hôpital Saint-Louis (FR)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
- Stanford University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-04-22
- DOI
- https://doi.org/10.64898/2026.04.20.719660
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- V Foundation for Cancer Research
- California Institute of Regenerative Medicine