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- Title
CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors.
- Authors
Jin, Linchun; Tao, Haipeng; Karachi, Aida; Long, Yu; Hou, Alicia Y.; Na, Meng; Dyson, Kyle A.; Grippin, Adam J.; Deleyrolle, Loic P.; Zhang, Wang; Rajon, Didier A.; Wang, Qiong J.; Yang, James C.; Kresak, Jesse L.; Sayour, Elias J.; Rahman, Maryam; Bova, Frank J.; Lin, Zhiguo; Mitchell, Duane A.; Huang, Jianping
- Abstract
Chimeric antigen receptor (CAR) T-cell therapy targeting solid tumors has stagnated as a result of tumor heterogeneity, immunosuppressive microenvironments, and inadequate intratumoral T cell trafficking and persistence. Early (≤3 days) intratumoral presentation of CAR T cells post-treatment is a superior predictor of survival than peripheral persistence. Therefore, we have co-opted IL-8 release from tumors to enhance intratumoral T-cell trafficking through a CAR design for maximal antitumor activity in solid tumors. Here, we demonstrate that IL-8 receptor, CXCR1 or CXCR2, modified CARs markedly enhance migration and persistence of T cells in the tumor, which induce complete tumor regression and long-lasting immunologic memory in pre-clinical models of aggressive tumors such as glioblastoma, ovarian and pancreatic cancer. CAR T-cell therapy efficacy in solid tumors is limited by inadequate T-cell migration and/or persistence in tumour microenvironment. Here, the authors show that the activity of tumour-antigen specific CAR T cells, in multiple preclinical mouse models, can be enhanced by co-expression of two IL-8 receptors that mediate their migration into the tumor microenvironment when IL-8 production in tumor is naturally expressed or enhanced by radiation.
- Subjects
T cell receptors; T cells; CHIMERIC antigen receptors; CYTOTOXIC T cells; IMMUNOLOGIC memory; TUMORS; ANIMAL models in research; PANCREATIC cancer
- Publication
Nature Communications, 2019, Vol 10, Issue 1, pN.PAG
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-11869-4