Assessing resistance mechanisms in synNotch-CAR T cell-mediated glioblastoma therapy and evaluation of potential mitigation strategies

评估 synNotch-CAR T 细胞介导的胶质母细胞瘤治疗的耐药机制并评估潜在的缓解策略

• 批准号: 516778857
• 负责人: Dr. Marco Gallus
• 金额: --
• 依托单位: Department of Neurological Surgery
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/516778857?language=en
• 关键词: Assessing; resistance; mechanisms; synNotch; CAR

Glioblastoma (GBM) is the most common primary malignant brain tumor with a median overall survival of less than 2 years and a recurrence rate of nearly 100%. Therefore, new therapeutic strategies are urgently needed. Chimeric antigen receptor T cell (CAR T) therapy is promising, but several challenges such as lack of ideal target antigens, T cell exhaustion, and tumor-induced immunosuppression must be addressed. Recently, it was discovered that chimeric forms of Notch, a type 1 transmembrane protein, can serve as a general platform for the development of new cell-cell contact signaling pathways (Synthetic Notch "synNotch"). This enables the development of T cells that exhibit customized therapeutic response programs using synthetic Notch receptors. A new generation of innovative T cell circuits that recognize glioblastoma cells based on the "prime-and-kill" strategy has been developed. In this strategy, priming antigen expressed exclusively on brain or GBM cells is recognized by the synNotch receptor, thereby inducing the expression of a CAR (synNotch-CAR=SYNC). This offers the possibility of safely targeting low-specificity GBM antigens and is also associated with excellent T cell persistence in vivo. Although this new approach appears promising, it is not yet known how efficiently SYNC T cells work in an intact immune system. Recent studies have shown that counter-active immunoregulatory molecules such as programmed death-ligand 1 (PD-L1) and transforming growth factor ß1 (TGF-β1) appear to play a key role in tumor-induced immunosuppression. Therefore, studies combining SYNC-T cell therapy with blockade of these molecules in an intact immune system are now needed. The aim of this study is to investigate potential resistance mechanisms of SYNC T cell therapy in immunocompetent C57BL/6 mice bearing EGFRvIII-expressing brain tumors of the low-immunogenic SB28 mouse glioma cell line. B-SYNC T cells developed by the Okada laboratory will be used as therapy. These cells are primed by the CNS-specific antigen Brevican and express an anti-EGFRvIII CAR upon activation. The efficacy of B-SYNC therapy alone and in combination with intravenous infusion of monoclonal antibodies directed against PD-1 or TGF-ß1 will be investigated. As a subordinate goal, I will also determine whether anti-PD-1 or TGF-ß1 expression directly by the SYNC T cell itself can overcome potential local immunosuppression and may be superior to infusion of antibodies, when integrated as an additional payload in the synNotch circuit.

胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤，中位总生存期不到2年，复发率接近100%。因此，迫切需要新的治疗策略。嵌合抗原受体T细胞（CAR T）疗法前景广阔，但必须解决一些挑战，例如缺乏理想的靶抗原、T细胞耗竭和肿瘤诱导的免疫抑制。最近，人们发现Notch（一种1型跨膜蛋白）的嵌合形式可以作为开发新的细胞-细胞接触信号通路（合成Notch“synNotch”）的通用平台。这使得 T 细胞的开发能够利用合成的 Notch 受体表现出定制的治疗反应程序。新一代创新 T 细胞回路已开发出来，该回路可基于“引发并杀死”策略识别胶质母细胞瘤细胞。在该策略中，仅在脑或GBM细胞上表达的引发抗原被synNotch受体识别，从而诱导CAR的表达（synNotch-CAR=SYNC）。这提供了安全靶向低特异性 GBM 抗原的可能性，并且还与体内出色的 T 细胞持久性相关。尽管这种新方法看起来很有希望，但目前尚不清楚 SYNC T 细胞在完整免疫系统中的工作效率如何。最近的研究表明，程序性死亡配体 1 (PD-L1) 和转化生长因子 ß1 (TGF-β1) 等反作用免疫调节分子似乎在肿瘤诱导的免疫抑制中发挥着关键作用。因此，现在需要将 SYNC-T 细胞疗法与在完整免疫系统中阻断这些分子相结合的研究。本研究的目的是研究 SYNC T 细胞疗法在具有低免疫原性 SB28 小鼠神经胶质瘤细胞系的表达 EGFRvIII 脑肿瘤的免疫活性 C57BL/6 小鼠中的潜在耐药机制。冈田实验室开发的 B-SYNC T 细胞将用于治疗。这些细胞由 CNS 特异性抗原 Brevican 启动，并在激活后表达抗 EGFRvIII CAR。将研究单独使用 B-SYNC 疗法以及与静脉输注针对 PD-1 或​​ TGF-ß1 的单克隆抗体相结合的疗效。 作为次要目标，我还将确定 SYNC T 细胞本身直接表达抗 PD-1 或​​ TGF-ß1 是否可以克服潜在的局部免疫抑制，并且当作为附加有效负载集成到 synNotch 电路中时，是否可能优于抗体输注。