Targeting brain lesions of non-small cell lung cancer by enhancing CCL2-mediated CAR-T cell migration

Hongxia Li; Emily B Harrison; Huizhong Li; Koichi Hirabayashi; Jing Chen; Qi-Xiang Li; Jared Gunn; Jared Weiss; Barbara Savoldo; Joel S Parker; Chad V Pecot; Gianpietro Dotti; Hongwei Du

doi:10.1038/s41467-022-29647-0

Targeting brain lesions of non-small cell lung cancer by enhancing CCL2-mediated CAR-T cell migration

Nat Commun. 2022 Apr 20;13(1):2154. doi: 10.1038/s41467-022-29647-0.

Authors

Hongxia Li^{1

2}, Emily B Harrison^{1

3}, Huizhong Li^{1

4}, Koichi Hirabayashi¹, Jing Chen⁵, Qi-Xiang Li⁵, Jared Gunn⁵, Jared Weiss^{1

6

7}, Barbara Savoldo^{1

8}, Joel S Parker^{1

9}, Chad V Pecot^{1

6

7}, Gianpietro Dotti^{10

11}, Hongwei Du^{12

13}

Affiliations

¹ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
² Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
³ Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁴ Cancer Immunotherapy Center, Cancer Research Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China.
⁵ Crown Bioscience Inc, San Diego, CA, USA.
⁶ Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁷ Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁸ Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁹ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁰ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. gdotti@med.unc.edu.
¹¹ Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. gdotti@med.unc.edu.
¹² Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. hwdu@xzhmu.edu.cn.
¹³ Cancer Immunotherapy Center, Cancer Research Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, China. hwdu@xzhmu.edu.cn.

Abstract

Metastatic non-small cell lung cancer (NSCLC) remains largely incurable and the prognosis is extremely poor once it spreads to the brain. In particular, in patients with brain metastases, the blood brain barrier (BBB) remains a significant obstacle for the biodistribution of antitumor drugs and immune cells. Here we report that chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR) exhibit antitumor activity in vitro against tumor cell lines and lung cancer organoids, and in vivo in xenotransplant models of orthotopic and metastatic NSCLC. The co-expression of the CCL2 receptor CCR2b in B7-H3.CAR-T cells, significantly improves their capability of passing the BBB, providing enhanced antitumor activity against brain tumor lesions. These findings indicate that leveraging T-cell chemotaxis through CCR2b co-expression represents a strategy to improve the efficacy of adoptive T-cell therapies in patients with solid tumors presenting with brain metastases.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Brain / metabolism
Brain Neoplasms* / metabolism
Carcinoma, Non-Small-Cell Lung* / drug therapy
Cell Line, Tumor
Cell Movement
Chemokine CCL2 / genetics
Chemokine CCL2 / metabolism
Humans
Lung Neoplasms* / drug therapy
Receptors, Chimeric Antigen*
T-Lymphocytes
Tissue Distribution
Xenograft Model Antitumor Assays

Substances

CCL2 protein, human
Chemokine CCL2
Receptors, Chimeric Antigen

Abstract

Publication types

MeSH terms

Substances

Grants and funding