Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Department of Orthopedic Surgery, Allegheny Health Network, Pittsburgh, Pennsylvania, USA.
J Immunother Cancer. 2023 Jul;11(7). doi: 10.1136/jitc-2023-006780.
Immunotherapies are becoming front-line treatments for many advanced cancers, and combinations of two or more therapies are beginning to be investigated. Based on their individual antitumor capabilities, we sought to determine whether combination oncolytic virus (OV) and radiation therapy (RT) may improve cancer outcomes.
To investigate the activity of this combination therapy, we used in vitro mouse and human cancer cell lines as well as a mouse model of skin cancer. After initial results, we further included immune checkpoint blockade, whose addition constituted a triple combination immunotherapy.
Our findings demonstrate that OV and RT reduce tumor growth via conversion of immunologically 'cold' tumors to 'hot', via a CD8+ T cell-dependent and IL-1α-dependent mechanism that is associated with increased PD-1/PD-L1 expression, and the triple combination of OV, RT, and PD-1 checkpoint inhibition impedes tumor growth and prolongs survival. Further, we describe the response of a PD-1-refractory patient with cutaneous squamous cell carcinoma who received the triple combination of OV, RT, and immune checkpoint inhibitor (ICI), and went on to experience unexpected, prolonged control and survival. He remains off-treatment and is without evidence of progression for >44 months since study entry.
Effective systemic antitumor immune response is rarely elicited by a single therapy. In a skin cancer mouse model, we demonstrate improved outcomes with combination OV, RT, and ICI treatment, which is associated with mechanisms involving augmented CD8+ T cell infiltration and IL-1α expression. We report tumor reduction and prolonged survival of a patient with skin cancer treated with combination OV, RT, and ICI. Overall, our data provide strong rationale for combining OV, RT, and ICI for treatment of patients with ICI-refractory skin and potentially other cancers.
免疫疗法正在成为许多晚期癌症的一线治疗方法，并且已经开始研究两种或更多疗法的联合应用。基于它们各自的抗肿瘤能力，我们试图确定联合溶瘤病毒（OV）和放射治疗（RT）是否可以改善癌症的治疗效果。
为了研究这种联合治疗的效果，我们使用了体外的小鼠和人类癌细胞系以及皮肤癌小鼠模型。在最初的结果之后，我们进一步加入了免疫检查点抑制剂，其加入构成了三重联合免疫治疗。
我们的研究结果表明，OV 和 RT 通过将免疫“冷”肿瘤转化为“热”肿瘤来减少肿瘤生长，这是一种依赖于 CD8+T 细胞和 IL-1α 的机制，与 PD-1/PD-L1 表达的增加有关，并且 OV、RT 和 PD-1 检查点抑制的三重联合可抑制肿瘤生长并延长生存期。此外，我们描述了一名患有皮肤鳞状细胞癌的 PD-1 耐药患者对 OV、RT 和免疫检查点抑制剂（ICI）三重联合治疗的反应，他经历了出乎意料的、持久的控制和生存。自研究开始以来，他已经停药 44 多个月，没有疾病进展的迹象。
有效的全身抗肿瘤免疫反应很少由单一疗法引起。在皮肤癌小鼠模型中，我们证明了联合 OV、RT 和 ICI 治疗可改善治疗效果，这与涉及增强 CD8+T 细胞浸润和 IL-1α 表达的机制有关。我们报告了一名患有皮肤癌的患者接受 OV、RT 和 ICI 联合治疗后肿瘤缩小和生存时间延长。总体而言，我们的数据为 OV、RT 和 ICI 联合治疗 ICI 耐药的皮肤癌和潜在的其他癌症患者提供了强有力的依据。
