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Recent work showed that precise insertion of a CAR at a defined locus improves treatment outcomes in the context of a CD19 CAR; however, it is unclear if such a strategy could also affect outcomes in solid tumors. Furthermore, CAR manufacturing generally relies on viral vectors for gene delivery, which comprise a complex and resource-intensive part of the manufacturing supply chain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Anti-GD2 CAR T cells were generated using CRISPR\/Cas9 within 9\u2009days using recombinant Cas9 protein and nucleic acids, without any viral vectors. The CAR was specifically targeted to the T cell receptor alpha constant gene (\n                      <jats:italic>TRAC<\/jats:italic>\n                      ). T cell products were characterized at the level of the genome, transcriptome, proteome, and secretome using CHANGE-seq, targeted next-generation sequencing, scRNA-seq, spectral cytometry, and ELISA assays, respectively. Functionality was evaluated\n                      <jats:italic>in vivo<\/jats:italic>\n                      in an NSG\u2122 xenograft neuroblastoma model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In comparison to retroviral CAR T cells, virus-free CRISPR CAR (VFC-CAR) T cells exhibit\n                      <jats:italic>TRAC<\/jats:italic>\n                      -targeted genomic integration of the CAR transgene, elevation of transcriptional and protein characteristics associated with a memory-like phenotype, and low tonic signaling prior to infusion arising in part from the knockout of the T cell receptor. On exposure to the GD2 target antigen, anti-GD2 VFC-CAR T cells exhibit specific cytotoxicity against GD2+ cells\u2009\n                      <jats:italic>in vitro<\/jats:italic>\n                      and induce solid tumor regression\n                      <jats:italic>in vivo<\/jats:italic>\n                      . VFC-CAR T cells demonstrate robust homing and persistence and decreased exhaustion relative to retroviral CAR T cells against a human neuroblastoma xenograft model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This study leverages virus-free genome editing technology to generate CAR T cells featuring a\n                      <jats:italic>TRAC<\/jats:italic>\n                      -targeted CAR, which could inform manufacturing of CAR T cells to treat cancers, including solid tumors.\n                    <\/jats:p>\n                  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