Therapeutic potential of CRISPR/Cas9 gene editing in engineered T‐cell therapy

Abstract

Cancer patients have been treated with various types of therapies, including conventional strategies like chemo‐, radio‐, and targeted therapy, as well as immunotherapy like checkpoint inhibitors, vaccine and cell therapy etc. Among the therapeutic alternatives, T‐cell therapy like CAR‐T (Chimeric Antigen Receptor Engineered T cell) and TCR‐T (T Cell Receptor Engineered T cell), has emerged as the most promising therapeutics due to its impressive clinical efficacy. However, there are many challenges and obstacles, such as immunosuppressive tumor microenvironment, manufacturing complexity, and poor infiltration of engrafted cells, etc still, need to be overcome for further treatment with different forms of cancer. Recently, the antitumor activities of CAR‐T and TCR‐T cells have shown great improvement with the utilization of CRISPR/Cas9 gene editing technology. Thus, the genome editing system could be a powerful genetic tool to use for manipulating T cells and enhancing the efficacy of cell immunotherapy. This review focuses on pros and cons of various gene delivery methods, challenges, and safety issues of CRISPR/Cas9 gene editing application in T‐cell‐based immunotherapy.

The Perfect Combination: Enhancing Patient Response to PD-1-Based Therapies in Epithelial Ovarian Cancer

“…The authors then performed a dual blockade of LAG-3 and CTLA-4 in PD-1 knockout mice, which resulted in an increase in tumor free survival to 40% of mice, as well as an increase of peritoneal CD8+ T cells and cytokine producing effector T cells, and a decrease in T regs and MDCS [ 104 ]. This study emphasizes the authority of the PD-1 pathway in EOC and demonstrates proof-of-principle for the potential development of therapeutics such as CAR-T cells with CRISPR-Cas9 editing of PD-1 [ 105 ]. To further support the dominance of the PD-1 pathway in EOC, Imai et al performed immune profiling in EOC patient ascites via flow cytometry and uncovered that out of all immune receptors studied (PD-1, LAG-3, TIM-3 and BTLA), PD-1 was expressed on the majority of CD4+ and CD8+ T cells, with median levels at 65.8% and 57.7%, respectively [ 106 ].…”

Transposon-Based CAR T Cells in Acute Leukemias: Where Are We Going?

“…In view of the shift of the "one batch one patient" paradigm (autologous products) towards "off-the-shelf" products [94], SB transposons satisfy all requirements for easier and more affordable CAR T-cell therapy. In this regard, gene editing such as CRISPR-CAS9 for the generation of universal CARs has started to be coupled to transposons, as a cutting-edge perspective that will surely further facilitate the current available genetic manipulation strategies [95].…”

CRISPR-Cas systems: Overview, innovations and applications in human disease research and gene therapy

“…Thereby, it could be used in multiple patients without causing graft versus host reaction (GVHR). In addition, CRISPR-Cas mediated genome editing has also been used to enhance the function of CAR-T cells by knocking out genes encoding signaling molecules or T cell inhibitory receptors, such as programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) [221] , [222] .…”