RT Journal Article
SR Electronic
T1 Optimization of T-cell Receptor–Modified T Cells for Cancer Therapy
JF Cancer Immunology Research
JO Cancer Immunol Res
FD American Association for Cancer Research
SP 743
OP 755
DO 10.1158/2326-6066.CIR-19-0910
VO 8
IS 6
A1 Drakes, Dylan J.
A1 Rafiq, Sarwish
A1 Purdon, Terence J.
A1 Lopez, Andrea V.
A1 Chandran, Smita S.
A1 Klebanoff, Christopher A.
A1 Brentjens, Renier J.
YR 2020
UL http://cancerimmunolres.aacrjournals.org/content/8/6/743.abstract
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