IND-enabling studies for a clinical trial to genetically program a persistent cancer-targeted immune system

Purpose: To improve persistence of adoptively transferred T cell receptor (TCR)-engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer (ACT) of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application. Experimental design: HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY-ESO-1 TCR were co-administered to myelodepleted HLA-A2/K^b mice within a formal GLP-compliant study to demonstrate safety, persistence and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, GMP-compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use. Results: TCR genetically-modified and ex vivo cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and co-administration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSCs differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality. Conclusion: Co-administration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this manuscript led to the U.S. FDA approval of IND 17471.

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