Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
J Immunother Cancer. 2020 Mar;8(1). doi: 10.1136/jitc-2020-000710.
Immune checkpoint blockade is arguably the most effective current cancer therapy approach; however, its efficacy is limited to patients with "hot" tumors, warranting an effective approach to transform "cold" tumors. Oncolytic viruses (especially properly armed ones) have positive effects on almost every aspect of the cancer-immunity cycle and can change the cancer-immune set point of a tumor. Here, we tested whether oncolytic vaccinia virus delivering tethered interleukin 12 (IL-12) could turn a "cold" tumor into a "hot" tumor while avoiding IL-12's systemic toxicity. Our data demonstrated that tethered IL-12 could be maintained in the tumor without treatment-induced toxic side effects. Moreover, the treatment facilitated tumor infiltration of more activated CD4 and CD8 T cells and less Tregs, granulocytic myeloid-derivedsuppressor cells, and exhausted CD8 T cells, with increased interferon γ and decreased transforming growth factor β, cyclooxygenase-2, and vascular endothelial growth factor expression, leading to transformed, immunogenic tumors and improved survival. Combined with programmed cell death 1 blockade, vaccinia virus expressing tethered IL-12 cured all mice with late-stage colon cancer, suggesting immediate translatability to the clinic.
免疫检查点阻断可被认为是目前最有效的癌症治疗方法；然而，其疗效仅限于“热”肿瘤患者，因此需要有效的方法来转化“冷”肿瘤。溶瘤病毒（特别是经过适当武装的病毒）对癌症免疫周期的几乎所有方面都有积极影响，并且可以改变肿瘤的癌症免疫设定点。在这里，我们测试了携带连接的白细胞介素 12（IL-12）的溶瘤痘病毒是否可以将“冷”肿瘤转化为“热”肿瘤，同时避免 IL-12 的全身毒性。我们的数据表明，连接的 IL-12 可以在没有治疗诱导的毒副作用的情况下在肿瘤中维持。此外，该治疗促进了更多激活的 CD4 和 CD8 T 细胞以及更少的 Tregs、粒细胞髓源性抑制细胞和耗竭的 CD8 T 细胞浸润肿瘤，同时增加干扰素 γ 和减少转化生长因子 β、环氧化酶-2 和血管内皮生长因子的表达，导致转化的免疫原性肿瘤和改善的生存。与程序性细胞死亡 1 阻断联合使用，表达连接的白细胞介素 12 的痘病毒治愈了所有患有晚期结肠癌的小鼠，表明可以立即转化为临床应用。
