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Tumor-Localized Interleukin-2 and Interleukin-12 Combine with Radiation Therapy to Safely Potentiate Regression of Advanced Malignant Melanoma in Pet Dogs

医学 黑色素瘤 细胞因子 放射治疗 免疫疗法 免疫系统 白细胞介素2 肿瘤科 病变 内科学 白细胞介素 毒性 肉瘤 癌症 病理 免疫学 癌症研究
作者
Jordan A. Stinson,Matheus Moreno P. Barbosa,Allison Sheen,Noor Momin,Elizabeth Fink,Jordan Hampel,Kim A. Selting,Rebecca Kamerer,Keith Bailey,K. Dane Wittrup,Timothy M. Fan
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
卷期号:: OF1-OF15 被引量:1
标识
DOI:10.1158/1078-0432.ccr-24-0861
摘要

Abstract Purpose: 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. Patients and Methods: 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. Results: 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. 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.
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