Biegert Greyson, Shaw Amanda Rosewell, Morita Daisuke, Porter Caroline, Matsumoto Ryu, Jatta Lisa, Crooks Noah, Woods Mae, Yao Qizhi Cathy, Parihar Robin, Suzuki Masataka
Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX, USA.
Mol Ther Oncol. 2025 May 26;33(2):201006. doi: 10.1016/j.omton.2025.201006. eCollection 2025 Jun 18.
Pancreatic ductal adenocarcinoma (PDAC) responds poorly to conventional treatments and immunotherapy. We previously developed a binary oncolytic/helper-dependent adenovirus system (CAd) that facilitated oncolysis and expressed the immunomodulatory molecule interleukin-12 and a programmed death ligand 1 (PD-L1) blocking mini-antibody. Given that CAd enhanced endogenous natural killer (NK) cell anti-tumor activity in humanized mice bearing PDAC tumors and that NK cells can be adoptively transferred to patients safely in the allogeneic setting, we hypothesized that a combination of CAd and allogeneic NK cells expressing a HER2-specific chimeric antigen receptor (HER2.CAR-NK) would be an effective, entirely "off-the-shelf" treatment against PDAC. We found that CAd-derived immunomodulatory molecules prolonged HER2.CAR-NK persistence at tumor sites, allowing long-term tumor growth control and improved survival in both humanized mice and a heterogeneous PDAC patient-derived xenografts (PDX) model. This effect was based on CAd-derived transgene support that shifted HER2.CAR-NK gene expression to that resembling an NK memory-like phenotype. Additionally, this allogeneic combination therapy was tolerated in humanized mice. Together, these data suggest that CAd and HER2.CAR-NK cell combination immunotherapy may be a novel and effective option for the treatment for immunologically "cold" PDAC tumors.
胰腺导管腺癌（PDAC）对传统治疗和免疫疗法反应不佳。我们之前开发了一种二元溶瘤/辅助依赖型腺病毒系统（CAd），该系统促进溶瘤作用，并表达免疫调节分子白细胞介素-12和一种程序性死亡配体1（PD-L1）阻断微型抗体。鉴于CAd增强了携带PDAC肿瘤的人源化小鼠体内内源性自然杀伤（NK）细胞的抗肿瘤活性，并且NK细胞可以在同种异体环境中安全地过继转移给患者，我们推测CAd与表达HER2特异性嵌合抗原受体（HER2.CAR-NK）的同种异体NK细胞联合使用将是一种有效的、完全“现成可用”的抗PDAC治疗方法。我们发现，CAd衍生的免疫调节分子延长了HER2.CAR-NK在肿瘤部位的持久性，从而实现了对人源化小鼠和异质性PDAC患者来源的异种移植（PDX）模型中肿瘤生长的长期控制并改善了生存情况。这种效应基于CAd衍生的转基因支持，该支持将HER2.CAR-NK的基因表达转变为类似于NK记忆样表型的表达。此外，这种同种异体联合疗法在人源化小鼠中是可耐受的。总之，这些数据表明，CAd与HER2.CAR-NK细胞联合免疫疗法可能是治疗免疫“冷”性PDAC肿瘤的一种新型有效选择。
