학술논문
IND-Enabling Studies for a Clinical Trial to Genetically Program a Persistent Cancer-Targeted Immune System
Document Type
article
Author
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
Source
Clinical Cancer Research. 25(3)
Subject
Language
Abstract
PurposeTo 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 designHSCs 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.ResultsTCR 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.ConclusionsCoadministration 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.