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. CrooksRoger 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, Antoni Ribas

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1000-1011
Number of pages12
JournalClinical Cancer Research
Issue number3
StatePublished - Feb 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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