T cell-focused cancer immunotherapy including checkpoint inhibitors and cell therapies has been rapidly evolving over the past decade. Nevertheless, there remains a major unmet medical need in oncology generally and immuno-oncology specifically. We have constructed an oncolytic adenovirus, Ad5/3-E2F-d24-aMUC1aCD3-IL-2 (TILT-322), which is armed with a human aMUC1aCD3 T cell engager and IL-2. TILT-322 treatment stimulated T cell cytotoxicity through the increased presence of granzyme B, perforin, and interferon-gamma. Additional immune profiling indicated TILT-322 increased gamma delta T cell activation and impacted other cell types such as natural killer cells and natural killer-like T cells that are traditionally involved in cancer immunotherapy. TILT-322 treatment also decreased the proportion of exhausted CD8 T cells as demarked by immune checkpoint expression in ovarian ascites samples. Overall, our data showed that TILT-322 treatment led to an enhanced T cell activation and reversed T cell exhaustion translating into high antitumor efficacy when given locally or intravenously. The analysis of blood and tumors isolated from an patient-derived ovarian cancer xenograft model suggested TILT-322 mediated tumor control through improved T cell functions. Therefore, TILT-322 is a promising novel anti-tumor agent for clinical translation.

中文翻译：

---

使用编码 MUC1 双特异性抗体接合剂和 IL-2 细胞因子的新型腺病毒克服卵巢癌腹水中的效应 T 细胞耗竭


以 T 细胞为中心的癌症免疫疗法（包括检查点抑制剂和细胞疗法）在过去十年中得到了迅速发展。然而，在一般肿瘤学和特别是免疫肿瘤学方面仍然存在重大未满足的医疗需求。我们构建了一种溶瘤腺病毒 Ad5/3-E2F-d24-aMUC1aCD3-IL-2 (TILT-322)，它配备了人类 aMUC1aCD3 T 细胞接合剂和 IL-2。 TILT-322 治疗通过增加颗粒酶 B、穿孔素和干扰素-γ 的存在来刺激 T 细胞的细胞毒性。额外的免疫分析表明 TILT-322 增加了 γδT 细胞的激活，并影响了其他细胞类型，例如传统上参与癌症免疫治疗的自然杀伤细胞和类自然杀伤 T 细胞。 TILT-322 治疗还降低了卵巢腹水样本中免疫检查点表达所标记的耗尽 CD8 T 细胞的比例。总体而言，我们的数据表明，局部或静脉注射时，TILT-322 治疗可增强 T 细胞活化并逆转 T 细胞耗竭，从而转化为高抗肿瘤功效。对从患者来源的卵巢癌异种移植模型中分离出的血液和肿瘤的分析表明，TILT-322 通过改善 T 细胞功能介导肿瘤控制。因此，TILT-322是一种有前景的临床转化新型抗肿瘤药物。