Managing allorejection in off-the-shelf CAR-engineered cell therapies

Yan-Ruide Li; Ying Fang; Siyue Niu; Yuning Chen; Zibai Lyu; Lili Yang

doi:10.1016/j.ymthe.2024.11.035

Managing allorejection in off-the-shelf CAR-engineered cell therapies

Mol Ther. 2024 Nov 26:S1525-0016(24)00762-7. doi: 10.1016/j.ymthe.2024.11.035. Online ahead of print.

Authors

Yan-Ruide Li¹, Ying Fang², Siyue Niu², Yuning Chen², Zibai Lyu², Lili Yang³

Affiliations

¹ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: charlie.li@ucla.edu.
² Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Parker Institute for Cancer Immunotherapy, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: liliyang@g.ucla.edu.

PMID: 39600090
DOI: 10.1016/j.ymthe.2024.11.035

Abstract

Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has revolutionized the treatment of various diseases, including cancers and autoimmune disorders. However, all US Food and Drug Administration (FDA)-approved CAR-T cell therapies are autologous, and their widespread clinical application is limited by several challenges, such as complex individualized manufacturing, high costs, and the need for patient-specific selection. Allogeneic off-the-shelf CAR-engineered cell therapy offers promising potential due to its immediate availability, consistent quality, potency, and scalability in manufacturing. Nonetheless, significant challenges, including the risks of graft-versus-host disease (GvHD) and host-cell-mediated allorejection, must be addressed. Strategies such as knocking out endogenous T cell receptors (TCRs) or using alternative therapeutic cells with low GvHD risk have shown promise in clinical trials aimed at reducing GvHD. However, mitigating allorejection remains critical for ensuring the long-term sustainability and efficacy of off-the-shelf cell products. In this review, we discuss the immunological basis of allorejection in CAR-engineered therapies and explore various strategies to overcome this challenge. We also highlight key insights from recent clinical trials, particularly related to the sustainability and immunogenicity of allogeneic CAR-engineered cell products, and address manufacturing considerations aimed at minimizing allorejection and optimizing the efficacy of this emerging therapeutic approach.

Keywords: B2M; CAR-T cells; CIITA; HLA; NK cells; allogeneic cell therapy; allorejection; beta-2-microglobulin; chimeric antigen receptor-engineered T cells; class II major histocompatibility complex transactivator; genetic engineering; human leukocyte antigen; natural killer cells; off-the-shelf cell therapy.

Publication types

Review