PD-1 blockade does not improve efficacy of EpCAM-directed CAR T-cell in lung cancer brain metastasis

Blobner, Jens; Dengler, Laura; Eberle, Constantin; Herold, Julika J.; Xu, Tao; Beck, Alexander; Mühlbauer, Anton; Müller, Katharina J.; Teske, Nico; Karschnia, Philipp; van den Heuvel, Dominic; Schallerer, Ferdinand; Ishikawa-Ankerhold, Hellen; Thon, Niklas; Tonn, Joerg-Christian; Subklewe, Marion; Kobold, Sebastian; Harter, Patrick N.; Buchholz, Veit R.; von Baumgarten, Louisa (2024): PD-1 blockade does not improve efficacy of EpCAM-directed CAR T-cell in lung cancer brain metastasis. Cancer Immunology, Immunotherapy, 73: 255. ISSN 1432-0851

Abstract

Background

Lung cancer brain metastasis has a devastating prognosis, necessitating innovative treatment strategies. While chimeric antigen receptor (CAR) T-cell show promise in hematologic malignancies, their efficacy in solid tumors, including brain metastasis, is limited by the immunosuppressive tumor environment. The PD-L1/PD-1 pathway inhibits CAR T-cell activity in the tumor microenvironment, presenting a potential target to enhance therapeutic efficacy. This study aims to evaluate the impact of anti-PD-1 antibodies on CAR T-cell in treating lung cancer brain metastasis.

Methods

We utilized a murine immunocompetent, syngeneic orthotopic cerebral metastasis model for repetitive intracerebral two-photon laser scanning microscopy, enabling in vivo characterization of red fluorescent tumor cells and CAR T-cell at a single-cell level over time. Red fluorescent EpCAM-transduced Lewis lung carcinoma cells ( EpCAM/tdt LL/2 cells) were implanted intracranially. Following the formation of brain metastasis, EpCAM-directed CAR T-cell were injected into adjacent brain tissue, and animals received either anti-PD-1 or an isotype control.

Results

Compared to controls receiving T-cell lacking a CAR, mice receiving EpCAM-directed CAR T-cell showed higher intratumoral CAR T-cell densities in the beginning after intraparenchymal injection. This finding was accompanied with reduced tumor growth and translated into a survival benefit. Additional anti-PD-1 treatment, however, did not affect intratumoral CAR T-cell persistence nor tumor growth and thereby did not provide an additional therapeutic effect.

Conclusion

CAR T-cell therapy for brain malignancies appears promising. However, additional anti-PD-1 treatment did not enhance intratumoral CAR T-cell persistence or effector function, highlighting the need for novel strategies to improve CAR T-cell therapy in solid tumors.

• Dokumententyp: Artikel (Klinikum der LMU)
• Organisationseinheit (Fakultäten): 07 Medizin > Klinikum der LMU München > Neurochirurgische Klinik und Poliklinik
• DFG-Fachsystematik der Wissenschaftsbereiche: Lebenswissenschaften
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 452881907
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 165054336