Genome Editing in Engineered T Cells for Cancer Immunotherapy

Abstract

Advanced gene transfer technologies and profound immunological insights have enabled substantial increases in the efficacy of anticancer adoptive cellular therapy (ACT). In recent years, the U.S. Food and Drug Administration and European Medicines Agency have approved six engineered T cell therapeutic products, all chimeric antigen receptor-engineered T cells directed against B cell malignancies. Despite encouraging clinical results, engineered T cell therapy is still constrained by challenges, which could be addressed by genome editing. As RNA-guided Clustered Regularly Interspaced Short Palindromic Repeats technology passes its 10-year anniversary, we review emerging applications of genome editing approaches designed to (1) overcome resistance to therapy, including cancer immune evasion mechanisms; (2) avoid unwanted immune reactions related to allogeneic T cell products; (3) increase fitness, expansion capacity, persistence, and potency of engineered T cells, while preserving their safety profile; and (4) improve the ability of therapeutic cells to resist immunosuppressive signals active in the tumor microenvironment. Overall, these innovative approaches should widen the safe and effective use of ACT to larger number of patients affected by cancer.

Keywords: CAR; CRISPR; TCR.

Figure 1.

Genome editing applied to T cells for cancer immunotherapy: applications. TALENs, HE, ZFNs, and CRISPR/Cas9 platforms, including BE system can be used to obtain permanent gene disruption and/or to promote targeted integration of a selected transgene in a preselected genomic region. A summary of some of the genes edited to date in the context of adoptive T cell therapy is reported, together with the specific nuclease system used. ARID1A, AT-Rich Interaction Domain 1A; B2m, B2-microglobulin; BATF3, basic leucine zipper ATF-like transcription factor 3; BEs, base editors; CAR, chimeric antigen receptor; cBAF, canonical BAF complex; CBLC, Cbl Proto-Oncogene C; CIITA, Class II Major Histocompatibility Complex Transactivator; DGK, diacylglycerol kinase; DNMT3A, DNA methyltransferase 3 alpha; EGR1, early growth response protein 1; FAM49B, family with sequence similarity 49, member B; HE, homing endonucleases; ID3, inhibitor of DNA binding 3; IFPs, immunomodulatory fusion proteins; INO80, chromatin-remodeling ATPase INO80; RFX5, regulator factor X5; SOX4, SRY-box transcription factor 4; TALENs, transcription activator-like effector nucleases; TCR, T cell receptor; TET2, tet methylcytosine dioxygenase 2; UBASH3A, Ubiquitin Associated and SH3 Domain Containing A; ZFNs, zinc finger nucleases.