PT  - JOURNAL ARTICLE
AU  - Drakes, Dylan J.
AU  - Rafiq, Sarwish
AU  - Purdon, Terence J.
AU  - Lopez, Andrea V.
AU  - Chandran, Smita S.
AU  - Klebanoff, Christopher A.
AU  - Brentjens, Renier J.
TI  - Optimization of T-cell Receptor–Modified T Cells for Cancer Therapy
AID  - 10.1158/2326-6066.CIR-19-0910
DP  - 2020 Jun 01
TA  - Cancer Immunology Research
PG  - 743--755
VI  - 8
IP  - 6
4099  - http://cancerimmunolres.aacrjournals.org/content/8/6/743.short
4100  - http://cancerimmunolres.aacrjournals.org/content/8/6/743.full
SO  - Cancer Immunol Res2020 Jun 01; 8
AB  - 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