Data_Sheet_1_Arming Anti-EGFRvIII CAR-T With TGFβ Trap Improves Antitumor Efficacy in Glioma Mouse Models.PDF

Glioblastoma (GBM) is an aggressive malignancy with poor prognosis. New therapeutic strategies for GBM are urgently needed. Although clinical studies have demonstrated the feasibility and safety of chimeric antigen receptor (CAR) T cell therapy for GBM, its efficacy has not been that impressive. The major limitation for anti-tumor efficacy of CAR-Ts is the immunosuppressive milieu of the GBM tumor microenvironment (TME). TGFβ, a substantial component in GBM, compromises the immune response and contributes to immune evasion and tumor progression. To overcome this limitation and improve the efficacy of CAR-T cells for GBM, we optimized an EGFRvIII-specific CAR construct with TGFRII ectodomain as a TGFβ-trap and generated TGFβ-resistant CAR-Ts for GBM therapy. We demonstrated that this TGFβ-trapped architecture enhanced anti-tumor efficacy of EGFRvIII-specific CAR-T and prolonged the survival of mice bearing GBM. In addition, the GBM-infiltrated microglia, typically considered tumorigenic, showed increased expression of M1 polarization markers after treatment with the TGFβ-trap CAR-Ts group, indicating that these microglia were polarized toward a pro-inflammatory and anti-tumorigenic phenotype. Overall, these results indicated that arming CAR-T cells with a TGFβ-trap diminishes the immunosuppressive effect and is a potential strategy to improve CAR-T efficacy for GBM therapy.

胶质母细胞瘤（GBM）是一种侵袭性恶性疾病，预后较差。针对GBM的新治疗方案亟待开发。尽管临床研究已经证实了嵌合抗原受体（CAR）T细胞疗法在GBM治疗中的可行性和安全性，但其疗效尚不令人满意。CAR-T细胞在肿瘤微环境（TME）中抗肿瘤疗效的主要限制因素是免疫抑制环境。TGFβ，GBM中的重要组成部分，损害免疫应答，并促成免疫逃逸和肿瘤进展。为了克服这一限制，提高CAR-T细胞在GBM治疗中的疗效，我们优化了一种EGFRvIII特异性CAR结构，其中TGFRII外泌体作为TGFβ捕获器，并生成了对TGFβ具有耐药性的CAR-T细胞用于GBM治疗。我们证实，这种TGFβ捕获的架构增强了EGFRvIII特异性CAR-T细胞的抗肿瘤疗效，并延长了携带GBM的小鼠的生存期。此外，GBM浸润的微胶质细胞，通常被认为是促肿瘤发生的，在接受TGFβ捕获CAR-T细胞治疗后，M1极化标记物的表达增加，表明这些微胶质细胞极化为促炎和抗肿瘤表型。总体而言，这些结果表明，为CAR-T细胞配备TGFβ捕获器可以减弱免疫抑制效应，是提高CAR-T细胞在GBM治疗中疗效的潜在策略。