CRISPR/Cas systems to overcome challenges in developing the next generation of T cells for cancer therapy

Dennis Huang; Matthew Miller; Bhaargavi Ashok; Samagra Jain; Nicholas A Peppas

doi:10.1016/j.addr.2020.07.015

CRISPR/Cas systems to overcome challenges in developing the next generation of T cells for cancer therapy

Adv Drug Deliv Rev. 2020:158:17-35. doi: 10.1016/j.addr.2020.07.015. Epub 2020 Jul 21.

Authors

Dennis Huang¹, Matthew Miller², Bhaargavi Ashok², Samagra Jain², Nicholas A Peppas³

Affiliations

¹ Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA.
² McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, TX 78712, USA.
³ Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, TX 78712, USA; Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA; Departments of Pediatrics and Surgery, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA. Electronic address: peppas@che.utexas.edu.

Abstract

Genetically engineered immune cells with chimeric antigen receptors (CAR) or modified T cell receptors (TCR) have demonstrated their potential as a potent class of new cancer therapeutic strategy. Despite the clinical success of autologous CD19 CAR T cells in hematological malignancies, allogeneic T cells exhibit many advantages over their autologous counterparts and have recently gathered widespread attention due to the emergence of multiplex genome editing techniques, particularly CRISPR/Cas systems. Furthermore, genetically engineered T cells face a host of major challenges in solid tumors that are not as significant for blood cancers such as T cell targeted delivery, target specificity, proliferation, persistence, and the immunosuppressive tumor microenvironment. We take this opportunity to analyze recent strategies to develop allogeneic T cells, specifically in consideration of CRISPR/Cas and its delivery systems for multiplex gene editing. Additionally, we discuss the current methods used to delivery CRISPR/Cas systems for immunotherapeutic applications, and the challenges to continued development of novel delivery systems. We also provide a comprehensive analysis of the major challenges that genetically engineered T cells face in solid tumors along with the most recent strategies to overcome these barriers, with an emphasis on CRISPR-based approaches. We illustrate the synergistic prospects for how the combination of synthetic biology and immune-oncology could pave the way for designing the next generation of precision cancer therapy.

Keywords: Adoptive cell therapy; Allogeneic T cells; CRISPR/Cas delivery systems; Cancer immunotherapy; Chimeric antigen receptor; Solid tumor.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Systematic Review

MeSH terms

CRISPR-Cas Systems / physiology*
Gene Editing / methods*
Humans
Immunotherapy, Adoptive / methods*
Neoplasms / drug therapy*
Receptors, Antigen, T-Cell / immunology
Receptors, Chimeric Antigen / immunology*
T-Lymphocytes / immunology

Substances

Receptors, Antigen, T-Cell
Receptors, Chimeric Antigen

Grants and funding

R01 EB022025/EB/NIBIB NIH HHS/United States