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IND-Enabling Studies for a Clinical Trial to Genetically Program a Persistent Cancer-Targeted Immune System.

  • Author(s): 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
  • et al.

Published Web Location

http://clincancerres.aacrjournals.org/content/early/2018/11/08/1078-0432.CCR-18-0963.long
No data is associated with this publication.
Abstract

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.

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