Rosewell Shaw Amanda, Morita Daisuke, Porter Caroline E, Tu Eric, Biegert Greyson W, Agrawal Sonia, Durham Nicholas, Brenner Malcolm K, 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. 2024 Oct 28;32(4):200899. doi: 10.1016/j.omton.2024.200899. eCollection 2024 Dec 19.
Systemic administration of oncolytic viruses (OVs) is a promising approach for targeting metastatic solid tumors, but their anti-tumor activity is limited by pre-existing neutralizing antibodies against common human viruses. Therefore, investigators have developed OVs derived from non-human host viruses. Successful implementation of this strategy requires that the viral vector selectively infects and replicates within human cancer cells. Newcastle disease virus (NDV) is an avian paramyxovirus that, as NDV-based OVs (oNDVs), has demonstrated safety and activity against multiple human tumors in clinical trials. Their use as a single agent, however, is insufficient to cure tumors. Similarly, chimeric antigen receptor-modified T cells (CAR-T cells) enable systemic targeting of cancer cells but have limited anti-tumor effects against bulky solid tumors, in part due to the immunosuppressive tumor environment. In this study, we evaluated the anti-tumor effects of combining systemic oNDV and CAR-T cell treatments. In models of non-small cell lung carcinoma (NSCLC), we found that oNDV itself and interleukin (IL)-12 derived from oNDVs enhance HER2-directed CAR-T cell anti-tumor activity and persistence and , leading to superior control of NSCLC tumors compared with either agent alone . Our data indicate that oNDV enhances the anti-tumor effects of HER2.CAR-T cells, thus controlling the growth of orthotopic NSCLC tumors.
溶瘤病毒（OVs）的全身给药是一种靶向转移性实体瘤的有前景的方法，但其抗肿瘤活性受到针对常见人类病毒的预先存在的中和抗体的限制。因此，研究人员开发了源自非人类宿主病毒的OVs。该策略的成功实施要求病毒载体在人类癌细胞内选择性感染并复制。新城疫病毒（NDV）是一种禽副粘病毒，作为基于NDV的OVs（oNDVs），在临床试验中已证明对多种人类肿瘤具有安全性和活性。然而，将它们作为单一药物使用不足以治愈肿瘤。同样，嵌合抗原受体修饰的T细胞（CAR-T细胞）能够全身靶向癌细胞，但对体积较大的实体瘤的抗肿瘤作用有限，部分原因是免疫抑制性肿瘤环境。在本研究中，我们评估了全身应用oNDV和CAR-T细胞联合治疗的抗肿瘤效果。在非小细胞肺癌（NSCLC）模型中，我们发现oNDV本身以及源自oNDV的白细胞介素（IL）-12可增强HER2导向的CAR-T细胞的抗肿瘤活性和持久性，与单独使用任何一种药物相比，能更好地控制NSCLC肿瘤。我们的数据表明，oNDV可增强HER2.CAR-T细胞的抗肿瘤作用，从而控制原位NSCLC肿瘤的生长。
