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Updated: Sep 26, 2025
Intracranial Cannula Implantation for Serial Locoregional Chimeric Antigen Receptor CAR T Cell Infusions in Mice
Published on: February 24, 2023
Targeting brain lesions of non-small cell lung cancer by enhancing CCL2-mediated CAR-T cell migration
Hongxia Li1,2, Emily B Harrison1,3, Huizhong Li1,4
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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.
Insights
Chimeric antigen receptor (CAR) T cells targeting B7-H3 show promise against metastatic non-small cell lung cancer (NSCLC). Co-expressing CCR2b enhances CAR T-cell ability to cross the blood-brain barrier, improving treatment for brain metastases.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Therapy
Background:
- Metastatic non-small cell lung cancer (NSCLC) has a poor prognosis, especially with brain metastases.
- The blood-brain barrier (BBB) limits drug and immune cell delivery to brain tumors.
- B7-H3 is a target antigen found on various solid tumors, including NSCLC.
Purpose of the Study:
- To evaluate the efficacy of B7-H3-targeted chimeric antigen receptor (CAR) T cells against NSCLC.
- To investigate if co-expressing the chemokine receptor CCR2b enhances CAR T-cell infiltration across the BBB.
- To determine the potential of this approach for treating brain metastases in NSCLC.
Main Methods:
- Development of B7-H3-targeted CAR T cells (B7-H3.CAR).
- In vitro testing against NSCLC cell lines and organoids.
- In vivo studies using xenotransplant models of orthotopic and metastatic NSCLC.
- Assessment of B7-H3.CAR T cells engineered with CCR2b for BBB penetration and anti-tumor activity.
Main Results:
- B7-H3.CAR T cells demonstrated in vitro antitumor activity.
- In vivo studies showed antitumor effects in orthotopic and metastatic NSCLC models.
- Co-expression of CCR2b significantly improved B7-H3.CAR T-cell ability to cross the BBB.
- Enhanced CAR T-cell infiltration led to improved antitumor activity against brain metastases.
Conclusions:
- B7-H3.CAR T cells are effective against NSCLC in preclinical models.
- CCR2b co-expression is a viable strategy to overcome the BBB challenge in CAR T-cell therapy.
- This approach holds promise for improving adoptive T-cell therapy for solid tumors with brain metastases.
