Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Clin Cancer Res. 2024 Sep 13;30(18):4029-4043. doi: 10.1158/1078-0432.CCR-24-0861.
Cytokines IL2 and IL12 exhibit potent anticancer 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 in dogs with advanced melanoma.
This study examined 15 client-owned dogs with histologically or cytologically confirmed malignant melanoma that received a single 9-Gy fraction of radiotherapy, followed by six cycles of combined collagen-anchored IL2 and IL12 therapy every 2 weeks. 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.
Median survival regardless of the 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%) had partial responses across their combined lesions, which is evidence of locoregional response. Profiling by NanoString of treatment-resistant dogs revealed that B2m loss was predictive of poor response to this therapy.
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.
细胞因子 IL2 和 IL12 具有强大的抗癌活性，但由于肿瘤外免疫细胞的激活，其治疗窗口较窄。通过工程改造使细胞因子具有在肿瘤内注射后与肿瘤胶原结合和关联的能力，可增强反应而不产生毒性，这在接受肉瘤治疗的宠物犬中是安全的。在此，我们试图在患有晚期黑色素瘤的犬中测试这种方法的疗效。
本研究检查了 15 只经组织学或细胞学证实患有恶性黑色素瘤的患犬，这些犬接受了单次 9-Gy 放射治疗，随后每 2 周接受 6 个周期的联合胶原锚定 IL2 和 IL12 治疗。细胞因子剂量遵循 3 + 3 剂量递增设计，初始细胞因子剂量来自于先前在犬肉瘤中的评估。该试验没有针对肿瘤分期或转移负担、年龄、体重或绝育状态排除标准。
无论肿瘤分期或剂量水平如何，中位生存时间为 256 天，13 只完成治疗的犬中有 10 只（76.9%）在治疗病变处有 CT 测量的肿瘤消退。在患有转移性疾病的犬中，13 只中有 8 只（61.5%）在其联合病变中有部分反应，这是局部反应的证据。对治疗耐药犬进行 NanoString 分析显示，B2m 缺失是对这种治疗反应不良的预测因素。
总的来说，这些结果证实了局部给予肿瘤锚定细胞因子与放射治疗相结合，能够增强区域性疾病部位的反应。这一证据支持了这种方法的临床转化，并强调了在犬癌症中进行比较研究的实用性。
