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

IF 4.6 2区 医学 Q2 IMMUNOLOGY Cancer Immunology, Immunotherapy Pub Date : 2024-10-03 DOI:10.1007/s00262-024-03837-9
Jens Blobner, Laura Dengler, Constantin Eberle, Julika J Herold, Tao Xu, Alexander Beck, Anton Mühlbauer, Katharina J Müller, Nico Teske, Philipp Karschnia, Dominic van den Heuvel, Ferdinand Schallerer, Hellen Ishikawa-Ankerhold, Niklas Thon, Joerg-Christian Tonn, Marion Subklewe, Sebastian Kobold, Patrick N Harter, Veit R Buchholz, Louisa von Baumgarten
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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/tdtLL/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.

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PD-1阻断不能提高EpCAM引导的CAR T细胞对肺癌脑转移的疗效。
背景:肺癌脑转移的预后极具破坏性,因此需要创新的治疗策略。虽然嵌合抗原受体(CAR)T细胞在血液恶性肿瘤中显示出良好的前景,但它们在实体瘤(包括脑转移瘤)中的疗效却受到免疫抑制性肿瘤环境的限制。PD-L1/PD-1 通路抑制 CAR T 细胞在肿瘤微环境中的活性,为提高疗效提供了潜在靶点。本研究旨在评估抗PD-1抗体对CAR T细胞治疗肺癌脑转移的影响:方法:我们利用小鼠免疫功能健全的同种异体正位脑转移模型进行重复脑内双光子激光扫描显微镜检查,从而在单细胞水平上对红色荧光肿瘤细胞和CAR T细胞随时间变化的情况进行体内表征。红色荧光 EpCAM 转化的 Lewis 肺癌细胞(EpCAM/tdtLL/2 细胞)被植入颅内。在脑转移形成后,将 EpCAM 引导的 CAR T 细胞注射到邻近的脑组织,动物接受抗 PD-1 或同型对照:结果:与接受缺乏CAR的T细胞的对照组相比,接受EpCAM定向CAR T细胞的小鼠在实质内注射后的初期表现出更高的瘤内CAR T细胞密度。这一发现伴随着肿瘤生长的减少,并转化为生存获益。然而,额外的抗PD-1治疗并没有影响瘤内CAR T细胞的持续性或肿瘤生长,因此也没有提供额外的治疗效果:结论:CAR T细胞疗法治疗脑部恶性肿瘤似乎很有前景。然而,额外的抗PD-1治疗并不能增强瘤内CAR T细胞的持久性或效应功能,这凸显出需要新的策略来改善CAR T细胞治疗实体瘤的效果。
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来源期刊
CiteScore
10.50
自引率
1.70%
发文量
207
审稿时长
1 months
期刊介绍: Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions. The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.
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