Intratumoral Cytokine Immunotherapy Studies in Companion Canine Cancer Models

项目摘要 这是一项新的mpi r01提案，将蛋白质工程用于免疫治疗。 (Wittrup，麻省理工学院)与比较肿瘤学/兽医学(Fan，UIUC)一起测试临床 放疗与肿瘤内细胞因子给药/滞留联合治疗宠物的策略 患有黑色素瘤的狗，在UIUC兽医诊所。我们已经制定了留住员工的战略 原位注射细胞因子(特别是IL-2和IL-12)，将其表达为与自然细胞的融合 胶原结合域。这种方法已经被发现在挑战中是安全的治愈方法 小鼠移植和宝石瘤模型，现在将推进到更忠实的模型 人类癌症：自发性犬类黑色素瘤。这些肿瘤自发地出现在 繁殖的种群，并在临床之前经历免疫编辑的自然进化 演示文稿。犬黑色素瘤表现出与人类黑色素瘤相似的病理生理学特征，包括 免疫浸润型、排斥型和沙漠亚型的存在。在目标1中，我们将利用 对这些肿瘤进行更真实的解剖，以优化肿瘤内的微药物动力学 行政管理，建立关于可注射体积分数的基本原则， 针的类型和部位的数量。在目标2中，我们将测试治疗性假设 精确的时间编程的强烈局部细胞因子刺激可以是最佳的 与放射治疗相结合，以启动强大的T细胞疫苗反应 随之而来的系统性影响疗效。在目标3中，我们将在犬身上进行临床试验 黑色素瘤将严格比较瘤内细胞因子治疗的替代剂量方案 在辐射后。我们假设，细胞因子注射前的时间延迟将有一个 关键的，要么全有要么全无对结果的影响。这种学科间的合作已经开始， 文中给出了激动人心的初步处理数据。 该项目的首要目标是开发改进的人类癌症免疫疗法。 将肿瘤内免疫治疗与局部放射相结合的方案。多个先前版本 这一领域的临床试验还没有完全实现这种方法的前景，但通过执行 自发性犬黑色素瘤的快速设计-建造-测试-学习循环，我们希望收敛 更有效率地采取有效的策略。

Project Summary This is a new MPI R01 proposal bringing together protein engineering for immunotherapy (Wittrup, MIT) with comparative oncology/veterinary medicine (Fan, UIUC) to test clinical strategies for combining radiotherapy with intratumoral cytokine administration/retention in pet dogs with melanoma, at the UIUC veterinary clinic. We have developed a strategy for retaining injected cytokines (IL-2 and IL-12 in particular) in situ by expressing them as fusions to natural collagen-binding domains. This approach has been found to be safely curative in challenging murine transplant and GEM tumor models, and will now be advanced into a more faithful model for human cancer: spontaneous canine melanoma. These tumors arise spontaneously in outbred populations, and undergo a natural progression of immunoediting prior to clinical presentation. Canine melanoma exhibits pathophysiology similar to human melanoma, including the presence of immune infiltrated, excluded, and desert subtypes. In Aim 1, we will exploit the more-realistic anatomy of these tumors to optimize the micropharmacokinetics of intratumoral administration, establishing foundational principles with respect to injectable volume fractions, needle types, and numbers of sites. In Aim 2, we will test the therapeutic hypothesis that precisely temporally programmed intense localized cytokine stimulation can be optimally combined with radiation therapy so as to prime a strong T cell vaccinal response with consequent systemic impact on efficacy. In Aim 3, we will perform a clinical trial in canine melanoma to rigorously compare alternative dose scheduling for intratumoral cytokine therapy following irradiation. We hypothesize that the time delay prior to cytokine injection will have a critical, all-or-nothing effect on outcomes. This intradisciplinary collaboration has commenced, and exciting preliminary treatment data is presented herein. The overarching objective of this project is to develop improved human cancer immunotherapy protocols that combine intratumoral immunotherapy with local radiation. Multiple previous clinical trials in this area have yet to realize the full promise of this approach, but by performing rapid design-build-test-learn cycles in spontaneous canine melanoma, we hope to converge more efficiently to efficacious strategies.