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 () and Hongwei Du ()
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Hongxia Li: University of North Carolina at Chapel Hill
Emily B. Harrison: University of North Carolina at Chapel Hill
Huizhong Li: University of North Carolina at Chapel Hill
Koichi Hirabayashi: University of North Carolina at Chapel Hill
Jing Chen: Crown Bioscience Inc
Qi-Xiang Li: Crown Bioscience Inc
Jared Gunn: Crown Bioscience Inc
Jared Weiss: University of North Carolina at Chapel Hill
Barbara Savoldo: University of North Carolina at Chapel Hill
Joel S. Parker: University of North Carolina at Chapel Hill
Chad V. Pecot: University of North Carolina at Chapel Hill
Gianpietro Dotti: University of North Carolina at Chapel Hill
Hongwei Du: University of North Carolina at Chapel Hill

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29647-0

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