CRISPR-Cas9 gene editing provides a powerful tool to enhance the natural ability of human T cells to fight cancer. We report a first-in-human phase 1 clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCRα (TRAC) and TCRβ (TRBC), were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding programmed cell death protein 1 (PD-1; PDCD1), was performed to improve antitumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Although chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months, suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene editing for cancer immunotherapy.

Highlights d The tumor microenvironment induces tumor cells to produce retinoic acid d Retinoic acid skews monocyte differentiation toward macrophage rather than DC d Blocking retinoic acid production enhances anti-tumor T cell immunity d Pharmacological blockade of retinoic acid signaling synergizes with anti-PD-1 therapy

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The use of a vascularized fibula transfer combined with an intercalary allograft to reconstruct bone defects after tumor resection can prevent allograft nonunion and result in decreased time to bone healing, leading to earlier patient recovery and return of function.