Non-Viral CRISPR-Edited Neoantigen-Specific T Cells Traffic to Tumours in First-in-Human Solid Cancer Trial
This first-in-human phase 1 trial used non-viral CRISPR-Cas9 editing to simultaneously knock out endogenous TCR genes and knock in patient-specific neoantigen-targeting TCRs in T cells for 16 patients with refractory solid cancers. The personalised neoTCR T cells were detected in tumour biopsies at frequencies exceeding those of native tumour-reactive TCRs, demonstrating successful tumour trafficking. While clinical responses were modest, this study establishes the feasibility of a fully personalised, non-viral CRISPR cell therapy manufacturing pipeline from neoantigen discovery through clinical-grade production.
The original study
Non-viral precision T cell receptor replacement for personalized cell therapy.
- Authors
- Foy SP, Jacoby K, Bota DA, Hunter T, Pan Z, Stawiski E, et al.
- Journal
- Nature
- Type
- Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
- PMID
- 36356599
Original abstract
T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells1-3. Here we developed a clinical-grade approach based on CRISPR-Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encodes TCRβ). We also inserted into the TRAC locus two chains of a neoantigen-specific TCR (neoTCR) isolated from circulating T cells of patients. The neoTCRs were isolated using a personalized library of soluble predicted neoantigen-HLA capture reagents. Sixteen patients with different refractory solid cancers received up to three distinct neoTCR transgenic cell products. Each product expressed a patient-specific neoTCR and was administered in a cell-dose-escalation, first-in-human phase I clinical trial ( NCT03970382 ). One patient had grade 1 cytokine release syndrome and one patient had grade 3 encephalitis. All participants had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease and the other eleven had disease progression as the best response on the therapy. neoTCR transgenic T cells were detected in tumour biopsy samples after infusion at frequencies higher than the native TCRs before infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs that recognize mutational neoantigens. Moreover, simultaneous knockout of the endogenous TCR and knock-in of neoTCRs using single-step, non-viral precision genome-editing are achieved. The manufacture of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene-edited neoTCR T cell products and the ability of the transgenic T cells to traffic to the tumours of patients are also demonstrated.