Optimization of T-cell Receptor-Modified T Cells for Cancer Therapy

• Type of Material: Article
• Authors: Dylan J. Drakes, Weill Cornell Graduate School of Medical Sciences; Sarwish Rafiq, Emory University; Terence J. Purdon, Memorial Sloan Kettering Cancer Center; Andrea V. Lopez, Memorial Sloan Kettering Cancer Center; Smita S. Chandran, Memorial Sloan Kettering Cancer Center; Christopher A. Klebanoff, Memorial Sloan Kettering Cancer Center; Renier J. Brentjens, Weill Cornell Graduate School of Medical Sciences
• Language: English
• Date: 2020-06-01
• Publisher: AMER ASSOC CANCER RESEARCH
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2020
• Final Published Version (URL): http://dx.doi.org/10.1158/2326-6066.CIR-19-0910
• Title of Journal or Parent Work: CANCER IMMUNOLOGY RESEARCH
• Volume: 8
• Issue: 6
• Start Page: 743
• End Page: 755
• Grant/Funding Information: Supported by US NIH grants 5 P01 CA190174-03 (R.J.B.), 5 P50 CA192937-02 (R.J.B.), and T32 GM073546-11 (D.J.D.), The Annual Terry Fox Run for Cancer Research (R.J.B.), Kate’s Team (R.J.B.), Carson Family Charitable Trust (R.J.B.), Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research (R.J.B. and C.A.K.); the Experimental Therapeutics Center of MSKCC (R.J.B., S.S.C., and C.A.K.). S.S.C. and C.A.K. are also supported by the Parker Institute for Cancer Immunotherapy, the Damon Runyon Cancer Research Foundation, NCI/NIH RFA-CA-18-003 R33, the Breast Cancer Alliance, The Manhasset Women’s Coalition Against Breast Cancer, and the MSKCC Core grant P30 CA008748.
• Keywords: TCR; Science & Technology; IL-12; VECTOR DESIGN; 3RD SIGNAL; ACTIVATION; TOXICITY; REGRESSION; Oncology; ENHANCED ANTITUMOR-ACTIVITY; MOLECULAR-MECHANISMS; Life Sciences & Biomedicine; Immunology; LYMPHOCYTES
• Research Categories: Health Sciences, Immunology; Health Sciences, Oncology; Health Sciences, Public Health

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 TCRmodified 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). Tumortargeted 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 Tcell cancer therapy through expression of IL18.