Puig-Saus, CristinaParisi, GiuliaGarcia-Diaz, AngelKrystofinski, Paige E.Sandoval, SalemizZhang, RuixueChamphekar, Ameya S.McCabe, JamesCheung-Lau, Gardenia C.Truong, Nhat A.Vega-Crespo, AgustinKomenan, Marie Desiles S.Pang, JiaMacabali, Mignonette H.Saco, Justin D.Goodwin, Jeffrey L.Bolon, BradSeet, Christopher S.Montel-Hagen, AmelieCrooks, Gay M.Hollis, Roger P.Campo-Fernandez, BeatrizBischof, DanielaCornetta, KennethGschweng, Eric H.Adelson, CeliaNguyen, AlexanderYang, LiliWitte, Owen N.Baltimore, DavidComin-Anduix, BegonyaKohn, Donald B.Wang, XiaoyanCabrera, PaulaKaplan-Lefko, Paula J.Berent-Maoz, BeataRibas, Antoni2020-04-092020-04-092019-02-01Puig-Saus, C., Parisi, G., Garcia-Diaz, A., Krystofinski, P. E., Sandoval, S., Zhang, R., Champhekar, A. S., McCabe, J., Cheung-Lau, G. C., Truong, N. A., Vega-Crespo, A., Komenan, M., Pang, J., Macabali, M. H., Saco, J. D., Goodwin, J. L., Bolon, B., Seet, C. S., Montel-Hagen, A., Crooks, G. M., … Ribas, A. (2019). IND-Enabling Studies for a Clinical Trial to Genetically Program a Persistent Cancer-Targeted Immune System. Clinical cancer research : an official journal of the American Association for Cancer Research, 25(3), 1000–1011. https://doi.org/10.1158/1078-0432.CCR-18-0963https://hdl.handle.net/1805/22517PURPOSE: 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 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 coadministered to myelodepleted HLA-A2/Kb mice within a formal Good Laboratory Practice (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, Good Manufacturing Practice (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 coadministration 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 HSC's 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. CONCLUSIONS: Coadministration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this article led to the FDA approval of IND 17471.en-USPublisher PolicyNY-ESO-1 TCRAdoptive cell therapyGenetically modified hematopoietic stem cellsSafetyGene therapy investigational new drug (IND) applicationArticle