Improving CAR T cell therapy against malignancies through gene knock-down/out strategies: a systematic review.

BACKGROUND: CAR T cells still face numerous obstacles in treating hematologic and solid malignancies. Although gene editing technologies have improved CAR T cell therapy, there are currently no systematic reviews to broadly address preclinical and clinical outcomes of gene-edited CAR T cells. Therefore, we aimed to systematically review the preclinical and clinical studies that evaluate the outcomes of knocked-out/knocked-down (KO/KD) CAR T cells. METHODS: This study was submitted to international Prospective Register of Systematic Reviews (PROSPERO) with the ID CRD42022320541 and follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. We searched Five databases (PubMed, EMBASE, Cochrane Library, Web of Science, and Clinicaltrials.gov) up to March 19th, 2022 for the keywords of "CAR T cell" and "knock-out/knock-down". The retrieved records then underwent a two-step screening process based on the inclusion criteria, first title/abstract and then full-text screenings, and their data were used for qualitative synthesis. RESULTS: Our search results yielded 3780 records. Finally, a total of 241 records, including 193 animal and 52 human studies (four concurrent in both groups) that reported KO/KD genes for 105 proteins were included. The positive effects of these 105 KO/KD were categorized into five groups: (1) enabling allogeneic CAR production while limiting GVHD, (2) increasing the efficacy of CAR T cells, (3) Decreasing their side effects, (4) limiting CAR T cell fratricide, and (5) enabling the use of concurrent therapies. In the human section, solid tumors had fewer studies with less favorable outcomes compared to hematologic malignancies. CONCLUSIONS: This systematic review emphasized the various mechanisms by which CAR T cell effects could be boosted. Future researchers can choose their desired genes out of the 105 mentioned candidates. We also encourage the researchers to increase their efforts on solid tumors to compensate for the lack of increased efficacy in this group.