Overcoming ovarian cancer resistance and evasion to CAR-T cell therapy by harnessing allogeneic CAR-NKT cells

Yan-Ruide Li; Zhe Li; Yichen Zhu; Miao Li; Yuning Chen; Derek Lee; Christopher J Ochoa; Tanya Singh; Gabriella DiBernardo; Wenbin Guo; Shuo Li; Yang Zhou; Yanqi Yu; Adam Kramer; Matthew Wilson; Kuangyi Zhou; Zachary Spencer Dunn; Ying Fang; Jiaji Yu; Yu Jeong Kim; Jie Huang; Xinyuan Shen; Yu-Chen Wang; Ryan Hon; Taylor Basso; Evelynn Chen; Enbo Zhu; Siyu Lin; Adam Neal; Neda A Moatamed; Scott S Oh; Saeed Sadeghi; Calvin Pan; Aijun Wang; Aldons J Lusis; Xianghong Jasmine Zhou; Jin J Zhou; Matteo Pellegrini; Pin Wang; Sanaz Memarzadeh; Lili Yang

doi:10.1016/j.medj.2025.100804

Overcoming ovarian cancer resistance and evasion to CAR-T cell therapy by harnessing allogeneic CAR-NKT cells

Med. 2025 Oct 10;6(10):100804. doi: 10.1016/j.medj.2025.100804. Epub 2025 Aug 12.

Authors

Yan-Ruide Li¹, Zhe Li¹, Yichen Zhu¹, Miao Li¹, Yuning Chen¹, Derek Lee¹, Christopher J Ochoa², Tanya Singh³, Gabriella DiBernardo³, Wenbin Guo⁴, Shuo Li⁵, Yang Zhou¹, Yanqi Yu¹, Adam Kramer¹, Matthew Wilson¹, Kuangyi Zhou¹, Zachary Spencer Dunn⁶, Ying Fang¹, Jiaji Yu¹, Yu Jeong Kim¹, Jie Huang¹, Xinyuan Shen¹, Yu-Chen Wang⁷, Ryan Hon¹, Taylor Basso¹, Evelynn Chen¹, Enbo Zhu¹, Siyu Lin⁸, Adam Neal³, Neda A Moatamed⁵, Scott S Oh⁹, Saeed Sadeghi¹⁰, Calvin Pan⁷, Aijun Wang⁸, Aldons J Lusis¹¹, Xianghong Jasmine Zhou⁵, Jin J Zhou¹², Matteo Pellegrini¹³, Pin Wang¹⁴, Sanaz Memarzadeh¹⁵, Lili Yang¹⁶

Affiliations

¹ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA.
² Department of Obstetrics and Gynecology, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA.
³ Department of Obstetrics and Gynecology, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA.
⁴ Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA 90095, USA.
⁵ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
⁶ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA; Mork Family Department of Chemical Engineering and Materials Science, University of Southern California (USC), Los Angeles, CA 90089, USA.
⁷ Division of Cardiology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA.
⁸ Department of Biomedical Engineering, University of California, Davis (UCD), Davis, CA 95616, USA; Department of Surgery, School of Medicine, UCD, Sacramento, CA 95817, USA; Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Sacramento, CA 95817, USA.
⁹ Section of Interventional Pulmonology, Keck School of Medicine, USC, Los Angeles, CA 90089, USA.
¹⁰ Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
¹¹ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Division of Cardiology, Department of Medicine, UCLA, Los Angeles, CA 90095, USA; Human Genetics, UCLA, Los Angeles, CA 90095, USA.
¹² Department of Biostatistics, Fielding School of Public Health, UCLA, Los Angeles, CA 90095, USA.
¹³ Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA 90095, USA; Institute for Quantitative and Computational Biosciences-The Collaboratory, UCLA, Los Angeles, CA 90095, USA; Department of Molecular Cell and Developmental Biology, UCLA, Los Angeles, CA 90095, USA.
¹⁴ Mork Family Department of Chemical Engineering and Materials Science, University of Southern California (USC), Los Angeles, CA 90089, USA.
¹⁵ Department of Obstetrics and Gynecology, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; The VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA; Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA 90095, USA. Electronic address: smemarzadeh@mednet.ucla.edu.
¹⁶ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA 90095, USA; Department of Bioengineering, UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, UCLA, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA 90095, USA; Goodman-Luskin Microbiome Center, UCLA, Los Angeles, CA 90095, USA. Electronic address: liliyang@ucla.edu.

PMID: 40803321
DOI: 10.1016/j.medj.2025.100804

Abstract

Background: Ovarian cancer (OC) poses a significant challenge for conventional chimeric antigen receptor-engineered T (CAR-T) cell therapy, due to frequent recurrence linked to tumor heterogeneity, platinum resistance, immune evasion, and an immunosuppressive tumor microenvironment (TME).

Methods: Here, we analyze primary OC patient samples and identify a unique opportunity for allogeneic CAR-NKT (^AlloCAR-NKT) cells to concurrently attack OC tumor cells and their TME. Leveraging stem cell gene engineering and a clinically guided culture method, we achieve robust generation of ^AlloCAR-NKT cells at high yield and purity.

Findings: Compared to conventional CAR-T cells, ^AlloCAR-NKT cells demonstrate superior anti-OC efficacy, showcasing multiple OC-targeting mechanisms, focused tumor homing, and pronounced TME modulation. ^AlloCAR-NKT cells also exhibit a high safety profile with reduced cytokine release syndrome. Additionally, these cells do not induce graft-versus-host disease and resist host immune-cell-mediated allorejection.

Conclusions: These findings underscore the unique efficacy and safety advantages, as well as the off-the-shelf potential of ^AlloCAR-NKT cell therapy for OC.

Funding: Major funding was provided by the California Institute for Regenerative Medicine (CIRM).

Keywords: Pre-clinical research; allogeneic CAR-NKT cells; allorejection; cancer immunotherapy; cytokine release syndrome; graft-versus-host disease; hematopoietic stem and progenitor cells; invariant natural killer T cells; ovarian cancer; tumor immune resistance and evasion; tumor microenvironment.

MeSH terms

Animals
Female
Humans
Immunotherapy, Adoptive* / methods
Mice
Ovarian Neoplasms* / immunology
Ovarian Neoplasms* / therapy
Receptors, Chimeric Antigen* / immunology
Tumor Escape
Tumor Microenvironment / immunology

Substances

Receptors, Chimeric Antigen

Grants and funding

I01 BX006019/BX/BLRD VA/United States