Expressing IL-15/IL-18 and CXCR2 improve infiltration and survival of EGFRvIII-targeting CAR-T cells in breast cancer

Sun Ruixin; Liu Yifan; Wu Chuanlong; Zhou Min; Luo Hong; Du Guoxiu; Liu Zhengyang; Sun Yansha; Dong Yiwei; Su Jingwen; Fan Mingliang; Shi Bizhi; Jiang Hua; Li Zonghai

doi:10.1016/j.bcp.2023.115536

Expressing IL-15/IL-18 and CXCR2 improve infiltration and survival of EGFRvIII-targeting CAR-T cells in breast cancer

Biochem Pharmacol. 2023 Jun:212:115536. doi: 10.1016/j.bcp.2023.115536. Epub 2023 Apr 5.

Authors

Sun Ruixin¹, Liu Yifan², Wu Chuanlong³, Zhou Min², Luo Hong³, Du Guoxiu⁴, Liu Zhengyang², Sun Yansha², Dong Yiwei², Su Jingwen², Fan Mingliang², Shi Bizhi⁵, Jiang Hua⁶, Li Zonghai⁷

Affiliations

¹ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China; Department of Laboratory Medicine, Shanghai Tongji Hospital, School of Medicine, Tongji University, Shanghai 200065, China.
² State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China.
³ Department of Orthopaedics, Shanghai Key Laboratory for Prevention and Treatment of Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁴ CARsgen Therapeutics, Shanghai 200032, China.
⁵ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China; CARsgen Therapeutics, Shanghai 200032, China.
⁶ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China; CARsgen Therapeutics, Shanghai 200032, China. Electronic address: jianghuapy@163.com.
⁷ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China; CARsgen Therapeutics, Shanghai 200032, China. Electronic address: zonghaili@shsmu.edu.cn.

PMID: 37028461
DOI: 10.1016/j.bcp.2023.115536

Abstract

Previously, we have generated EGFRvIII-targeting CAR-T cells and brought hope for treating advanced breast cancer. However, EGFRvIII-targeting CAR-T cells were defined limited anti-tumor efficacy, which might be due to reduced accumulation, persistence of therapeutic T cells in tumor site of breast cancer. CXCLs were highly expressed in tumor environment of breast cancer and CXCR2 is the main receptor for CXCLs. Here, CXCR2 could significantly improve the trafficking and tumor specific accumulation of CAR-T cells both in vivo and in vitro. However, the anti-tumor effect of CXCR2 CAR-T cells were weaken which might be results of the apoptosis of T cells. Cytokines could stimulate Tcell proliferation, such as interleukin (IL)-15 and IL-18. Then, we generated CXCR2 CAR with synthetic IL-15 or IL-18 production. Co-expressing IL-15 or IL-18 could significantly suppress the exhaustion and apoptosis of T cells and enhanced the anti-tumor activity of CXCR2 CAR-T cells in vivo. Further, coexpression IL-15 or IL-18 in CXCR2 CAR-T cells did not cause toxicity. These findings provide a potential therapy strategy of co-expression IL-15 or IL-18 in CXCR2 CAR-T cells for the treatment of advancing breast cancer in the future.

Keywords: Breast cancer; CAR-T cells; CXCR2; Interleukin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms* / drug therapy
Female
Humans
Interleukin-15 / genetics
Interleukin-15 / therapeutic use
Interleukin-18* / genetics
T-Lymphocytes / pathology

Substances

epidermal growth factor receptor VIII
Interleukin-18
Interleukin-15