Skip to main content
eScholarship
Open Access Publications from the University of California

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

  • Author(s): Puig-Saus, C
  • Parisi, G
  • Garcia-Diaz, A
  • Krystofinski, PE
  • Sandoval, S
  • Zhang, R
  • Champhekar, AS
  • McCabe, J
  • Cheung-Lau, GC
  • Truong, NA
  • Vega-Crespo, A
  • Komenan, MDS
  • Pang, J
  • Macabali, MH
  • Saco, JD
  • Goodwin, JL
  • Bolon, B
  • Seet, CS
  • Montel-Hagen, A
  • Crooks, GM
  • Hollis, RP
  • Campo-Fernandez, B
  • Bischof, D
  • Cornetta, K
  • Gschweng, EH
  • Adelson, C
  • Nguyen, A
  • Yang, L
  • Witte, ON
  • Baltimore, D
  • Coming-Anduix, B
  • Kohn, DB
  • Wang, X
  • Cabrera, P
  • Kaplan-Lefko, PJ
  • Berent-Maoz, B
  • Ribas, A
  • 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 (ACT) 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 co-administered to myelodepleted HLA-A2/Kb mice within a formal 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, 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 co-administration 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 HSCs 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. CONCLUSION:Co-administration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this manuscript led to the U.S. FDA approval of IND 17471.

Many UC-authored scholarly publications are freely available on this site because of the UC Academic Senate's Open Access Policy. Let us know how this access is important for you.

Item not freely available? Link broken?
Report a problem accessing this item