Usurping TIGIT and CD73 activities with responsive, genetically-engineered NK cells as immunotherapy for glioblastoma

摘要 胶质母细胞瘤(GBM)是一种极具侵袭性的脑癌，只有不到5%的患者存活到 诊断后5年。GBM的微环境通过CD155的表达促进其发病。 它通过其配体TIGIT驱动对NK细胞效应器功能的抑制，并在低氧条件下产生 胞外酶CD73中的腺苷。腺苷反过来会削弱自然杀伤细胞(NK)的抗肿瘤功能。 细胞。因此，用过继转移的NK细胞进行的GBM免疫疗法可能会受到严重的 免疫抑制。为了改善对基底膜的治疗，本提案描述了一种 NK细胞的新型免疫疗法旨在以一种应答的方式共同靶向 TIGIT和CD73。我们建议通过使用合成的缺口信号来篡夺NK细胞上的TIGIT结合来实现这一点 并触发CD73抗体片段的局部释放。我们将对其抗肿瘤功能和GBM进行表征 这些细胞在原位GBM异种移植中的渗透并为这些同种异体细胞的使用提供依据 基因工程细胞作为一种安全、强大的免疫治疗手段。这个极具翻译性的项目建议 开发治疗基底膜的新型免疫疗法，有可能转化为有效的临床 在人类身上的治疗。

SUMMARY Glioblastoma (GBM) is an extremely aggressive brain cancer, with fewer than 5% of patients surviving to 5 years after diagnosis. The GBM microenvironment fuels its pathogenesis through the expression of CD155, which drives inhibition of NK cell effector functions via its ligand TIGIT, and the hypoxia-driven generation of adenosine from ectoenzyme CD73. Adenosine, in turns, impairs the anti-tumor function of natural killer (NK) cells. As a result, GBM immunotherapies with adoptively-transferred NK cells can be subject to severe immunosuppression. In order to improve the treatment of GBM, this proposal describes the development of a novel immunotherapy with NK cells engineered to co-target, in a responsive manner, the inhibitory functions of TIGIT and CD73. We propose to do so by engaging synthetic notch signaling to usurp TIGIT binding on NK cells and trigger the local release of CD73 antibody fragments. We will characterize the anti-tumor function and GBM infiltration of these cells in orthotopic GBM xenografts and make a case for the use of these allogeneic engineered cells as a safe, powerful immunotherapeutic modality. The highly translational project proposes to develop curative new immunotherapies for GBM which have the potential to be be translated into effective clinical treatments in humans.