Genetic engineering strategies to enhance antitumor reactivity and reduce alloreactivity for allogeneic cell-based cancer therapy

Yuning Chen; Yichen Zhu; Adam Kramer; Ying Fang; Matthew Wilson; Yan-Ruide Li; Lili Yang

doi:10.3389/fmed.2023.1135468

Genetic engineering strategies to enhance antitumor reactivity and reduce alloreactivity for allogeneic cell-based cancer therapy

Front Med (Lausanne). 2023 Mar 29:10:1135468. doi: 10.3389/fmed.2023.1135468. eCollection 2023.

Authors

Yuning Chen¹, Yichen Zhu¹, Adam Kramer¹, Ying Fang¹, Matthew Wilson¹, Yan-Ruide Li¹, Lili Yang^{1

2

3

4}

Affiliations

¹ Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, United States.
² Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, United States.
³ Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
⁴ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, United States.

Abstract

The realm of cell-based immunotherapy holds untapped potential for the development of next-generation cancer treatment through genetic engineering of chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapies for targeted eradication of cancerous malignancies. Such allogeneic "off-the-shelf" cell products can be advantageously manufactured in large quantities, stored for extended periods, and easily distributed to treat an exponential number of cancer patients. At current, patient risk of graft-versus-host disease (GvHD) and host-versus-graft (HvG) allorejection severely restrict the development of allogeneic CAR-T cell products. To address these limitations, a variety of genetic engineering strategies have been implemented to enhance antitumor efficacy, reduce GvHD and HvG onset, and improve the overall safety profile of T-cell based immunotherapies. In this review, we summarize these genetic engineering strategies and discuss the challenges and prospects these approaches provide to expedite progression of translational and clinical studies for adoption of a universal cell-based cancer immunotherapy.

Keywords: CRISPR-Cas9; allogeneic cell products; alloreactivity; cancer immunotherapy; chimeric antigen receptor-engineered T (CAR-T) cells; gene engineering; graft-versus-host disease; immune checkpoints.

Publication types

Review

Grants and funding

P30 CA016042/CA/NCI NIH HHS/United States