CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors

Linchun Jin, Haipeng Tao, Aida Karachi, Yu Long, Alicia Y. Hou, Meng Na, Kyle A. Dyson, Adam J. Grippin, Loic P. Deleyrolle, Wang Zhang, Didier A. Rajon, Qiong J. Wang, James C. Yang, Jesse L. Kresak, Elias J. Sayour, Maryam Rahman, Frank J. Bova, Zhiguo Lin, Duane A. Mitchell and Jianping Huang ()
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Linchun Jin: University of Florida
Haipeng Tao: Harbin Medical University
Aida Karachi: University of Florida
Yu Long: University of Florida
Alicia Y. Hou: University of Florida
Meng Na: Harbin Medical University
Kyle A. Dyson: University of Florida
Adam J. Grippin: University of Florida
Loic P. Deleyrolle: University of Florida
Wang Zhang: Harbin Medical University
Didier A. Rajon: University of Florida
Qiong J. Wang: The Surgery Branch, National Cancer Institute
James C. Yang: The Surgery Branch, National Cancer Institute
Jesse L. Kresak: University of Florida
Elias J. Sayour: University of Florida
Maryam Rahman: University of Florida
Frank J. Bova: University of Florida
Zhiguo Lin: Harbin Medical University
Duane A. Mitchell: University of Florida
Jianping Huang: University of Florida

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11869-4

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