Browsing by Author "Kaplan-Lefko, Paula J."

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    IND-Enabling Studies for a Clinical Trial to Genetically Program a Persistent Cancer-Targeted Immune System
    (American Association for Cancer Research, 2019-02-01) Puig-Saus, Cristina; Parisi, Giulia; Garcia-Diaz, Angel; Krystofinski, Paige E.; Sandoval, Salemiz; Zhang, Ruixue; Champhekar, Ameya S.; McCabe, James; Cheung-Lau, Gardenia C.; Truong, Nhat A.; Vega-Crespo, Agustin; Komenan, Marie Desiles S.; Pang, Jia; Macabali, Mignonette H.; Saco, Justin D.; Goodwin, Jeffrey L.; Bolon, Brad; Seet, Christopher S.; Montel-Hagen, Amelie; Crooks, Gay M.; Hollis, Roger P.; Campo-Fernandez, Beatriz; Bischof, Daniela; Cornetta, Kenneth; Gschweng, Eric H.; Adelson, Celia; Nguyen, Alexander; Yang, Lili; Witte, Owen N.; Baltimore, David; Comin-Anduix, Begonya; Kohn, Donald B.; Wang, Xiaoyan; Cabrera, Paula; Kaplan-Lefko, Paula J.; Berent-Maoz, Beata; Ribas, Antoni; Medical and Molecular Genetics, School of Medicine
    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 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.