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

Puig-Saus, Cristina and Baltimore, David (2019) IND-enabling studies for a clinical trial to genetically program a persistent cancer-targeted immune system. Clinical Cancer Research, 25 (3). pp. 1000-1011. ISSN 1078-0432. PMCID PMC6359988.

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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/K^b 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.

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Baltimore, David0000-0001-8723-8190
Additional Information:© 2018 American Association for Cancer Research. Received March 27, 2018; Revision received June 21, 2018; Accepted November 5, 2018; Published Online First: November 8, 2018. This work was funded by the California Institute for Regenerative Medicine (CIRM; A. Ribas), NCI grants P01 CA168585 and R35 CA197633 (A. Ribas), the PhaseOne Foundation (A. Ribas), the Caltech/UCLA Joint Center for Translational Medicine (D. Baltimore, O.N. Witte, and A. Ribas), the Ressler Family Fund, the Grimaldi Family Fund, the Samuels Family Fund, and the Garcia-Corsini Family Fund (A. Ribas). A. Ribas and O.N. Witte are members of the Parker Institute for Cancer Immunotherapy. We would like to acknowledge the support of the CIRM, the UCLA Broad Stem Cell Research Center, and the CIRM Alpha Stem Cell Clinic at UCLA. The National Gene Vector Biorepository (funded by a P40 grant from the NHLBI 9P40HL116242, K. Cornetta) provided cells and plasmids available in their repository and archive the test articles and specimens generated in the GLP studies. Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research Flow Cytometry Core Facility, which is supported by NIH awards CA-16042 and AI-28697, and the JCCC, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA. We thank Dr. Stephen T. Smale for his role as Test Facility Management in the GLP study, Dr. Richard C. Koya and Dr. Thinle Chodon for their support in the early stages of the project, all Division of Laboratory Animal Medicine (DLAM) personnel for their support with the animal work and GLP implementation, and Justin Tran for his help with the logistics of the project. The NY-ESO TCR used in this study is covered by patents including US 8,143,376 and is used under license from Adaptimmune Limited. As of September 7, 2017, GlaxoSmithKline plc (LSE:GSK) (NYSE:GSK) has exercised its option under a collaboration and license agreement signed in 2014 to exclusively license the right to research, develop, and commercialize Adaptimmune's NY-ESO SPEAR T-cell therapy program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funding AgencyGrant Number
California Institute for Regenerative Medicine (CIRM)UNSPECIFIED
NIHP01 CA168585
NIHR35 CA197633
PhaseOne FoundationUNSPECIFIED
Caltech-UCLA Joint Center for Translational Medicine UNSPECIFIED
Ressler Family FundUNSPECIFIED
Grimaldi Family FundUNSPECIFIED
Samuels Family FundUNSPECIFIED
Garcia-Corsini Family FundUNSPECIFIED
PubMed Central ID:PMC6359988
Record Number:CaltechAUTHORS:20181112-075749851
Persistent URL:
Official Citation:IND-Enabling Studies for a Clinical Trial to Genetically Program a Persistent Cancer-Targeted Immune System. Cristina Puig-Saus, Giulia Parisi, Angel Garcia-Diaz, Paige E. Krystofinski, Salemiz Sandoval, Ruixue Zhang, Ameya S. Champhekar, James McCabe, Gardenia C. Cheung-Lau, Nhat A. Truong, Agustin Vega-Crespo, Marie Desiles S. Komenan, Jia Pang, Mignonette H. Macabali, Justin D. Saco, Jeffrey L. Goodwin, Brad Bolon, Christopher S. Seet, Amelie Montel-Hagen, Gay M. Crooks, Roger P. Hollis, Beatriz Campo-Fernandez, Daniela Bischof, Kenneth Cornetta, Eric H. Gschweng, Celia Adelson, Alexander Nguyen, Lili Yang, Owen N. Witte, David Baltimore, Begonya Comin-Anduix, Donald B. Kohn, Xiaoyan Wang, Paula Cabrera, Paula J. Kaplan-Lefko, Beata Berent-Maoz and Antoni Ribas. Clin Cancer Res February 1 2019 (25) (3) 1000-1011; DOI: 10.1158/1078-0432.CCR-18-0963
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90826
Deposited By: Tony Diaz
Deposited On:13 Nov 2018 17:17
Last Modified:04 Feb 2019 21:49

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