Purpose: Interleukin-2 and -12 cytokines have potent anti-cancer activity, but suffer a narrow therapeutic window due to off-tumor immune cell activation. Engineering cytokines with the ability to bind and associate with tumor collagen after intratumoral injection potentiated response without toxicity in mice, and was previously safe in pet dogs with sarcoma. Here we sought to test the efficacy of this approach with in dogs with advanced melanoma. Experimental Design: This study examined fifteen client-owned dogs with histologically- or cytologically-confirmed malignant melanoma who received a single 9 Gray fraction of radiation therapy, followed by six cycles of combined collagen-anchored IL-2 and IL-12 therapy Q2W. Cytokine dosing followed a 3+3 dose escalation design, with the initial cytokine dose chosen from prior evaluation in canine sarcomas. No exclusion criteria for tumor stage or metastatic burden, age, weight, or neuter status were applied for this trial. Results: Median survival regardless of tumor stage or dose level was 256 days and 10/13 (76.9%) dogs that completed treatment had CT-measured tumor regression at the treated lesion. In dogs with metastatic disease, 8/13 (61.5%) dogs had partial responses across their combined lesions, evidence of locoregional response. Profiling by Nanostring of treatment-resistant dogs revealed that B2m loss was predictive of poor response to this therapy. Conclusions: Collectively, these results confirm the ability of locally administered tumor-anchored cytokines to potentiate responses at regional disease sites when combined with radiation. This evidence supports the clinical translation of this approach and highlights the utility of comparative investigation in canine cancers.

中文翻译：

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肿瘤局部白细胞介素 2 和白细胞介素 12 与放射治疗相结合，安全地增强宠物犬晚期恶性黑色素瘤的消退


目的：Interleukin-2 和 -12 细胞因子具有有效的抗癌活性，但由于肿瘤外免疫细胞激活而导致治疗窗口狭窄。肿瘤内注射后具有与肿瘤胶原结合和缔合能力的工程细胞因子可增强小鼠的反应而无毒性，并且以前在患有肉瘤的宠物狗中是安全的。在这里，我们试图测试这种方法对患有晚期黑色素瘤的狗的疗效。实验设计：本研究检查了 15 只客户拥有的经组织学或细胞学证实患有恶性黑色素瘤的狗，这些狗接受了单次 9 格雷部分的放射治疗，然后接受了 6 个周期的胶原锚定 IL-2 和 IL-12 联合治疗 Q2W。细胞因子剂量遵循3+3剂量递增设计，初始细胞因子剂量选自先前对犬肉瘤的评估。该试验没有应用肿瘤分期或转移负担、年龄、体重或中性状态的排除标准。结果：无论肿瘤分期或剂量水平如何，中位生存期均为 256 天，完成治疗的狗中有 10/13 (76.9%) 在治疗的病灶处出现 CT 测量的肿瘤消退。在患有转移性疾病的狗中，8/13 (61.5%) 的狗在其组合病变中出现部分反应，这是局部反应的证据。 Nanostring 对治疗耐药的狗进行的分析显示，B2m 损失预示着对该疗法的反应不佳。结论：总的来说，这些结果证实了局部施用的肿瘤锚定细胞因子与放射结合时能够增强区域疾病部位的反应。这一证据支持了这种方法的临床转化，并强调了比较研究在犬癌症中的实用性。