Optimization of T-cell receptor-modified T cells for cancer therapy Journal Article

Authors: Drakes, D. J.; Rafiq, S.; Purdon, T. J.; Lopez, A. V.; Chandran, S. S.; Klebanoff, C. A.; Brentjens, R. J.
Article Title: Optimization of T-cell receptor-modified T cells for cancer therapy
Abstract: T-cell receptor (TCR)-modified T-cell gene therapy can target a variety of extracellular and intracellular tumor-associated antigens, yet has had little clinical success. A potential explanation for limited antitumor efficacy is a lack of T-cell activation in vivo We postulated that expression of proinflammatory cytokines in TCR-modified T cells would activate T cells and enhance antitumor efficacy. We demonstrate that expression of interleukin 18 (IL18) in tumor-directed TCR-modified T cells provides a superior proinflammatory signal than expression of interleukin 12 (IL12). Tumor-targeted T cells secreting IL18 promote persistent and functional effector T cells and a proinflammatory tumor microenvironment. Together, these effects augmented overall survival of mice in the pmel-1 syngeneic tumor model. When combined with sublethal irradiation, IL18-secreting pmel-1 T cells were able to eradicate tumors, whereas IL12-secreting pmel-1 T cells caused toxicity in mice through excessive cytokine secretion. In another xenograft tumor model, IL18 secretion enhanced the persistence and antitumor efficacy of NY-ESO-1-reactive TCR-modified human T cells as well as overall survival of tumor-bearing mice. These results demonstrate a rationale for optimizing the efficacy of TCR-modified T-cell cancer therapy through expression of IL18.See related commentary by Wijewarnasuriya et al., p. 732. ©2020 American Association for Cancer Research.
Journal Title: Cancer Immunology Research
Volume: 8
Issue: 6
ISSN: 2326-6066
Publisher: American Association for Cancer Research  
Date Published: 2020-06-01
Start Page: 743
End Page: 755
Language: English
DOI: 10.1158/2326-6066.Cir-19-0910
PUBMED: 32209638
PROVIDER: scopus
PMCID: PMC7269835
Notes: Article -- Export Date: 1 July 2020 -- Source: Scopus
Citation Impact
MSK Authors
  1. Renier J Brentjens
    270 Brentjens
  2. Terence John Purdon
    58 Purdon
  3. Andrea V Lopez
    7 Lopez