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

Clin Cancer Res. 2019 Feb 1;25(3):1000-1011. doi: 10.1158/1078-0432.CCR-18-0963. Epub 2018 Nov 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, Neoplasm / genetics
  • Cells, Cultured
  • Clinical Trials as Topic
  • Drugs, Investigational / therapeutic use
  • Genetic Therapy / methods*
  • HLA-A2 Antigen / genetics
  • Hematopoietic Stem Cells / immunology*
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Membrane Proteins / genetics
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism


  • Antigens, Neoplasm
  • CTAG1B protein, human
  • Drugs, Investigational
  • HLA-A2 Antigen
  • Membrane Proteins
  • Receptors, Antigen, T-Cell