Intratumoral Cytokine Immunotherapy Studies in Companion Canine Cancer Models

项目摘要 这是一项新的MPI R 01提案，将蛋白质工程用于免疫治疗 （Wittrup，MIT）与比较肿瘤学/兽医学（Fan，UIUC）进行临床试验， PET中放射治疗与肿瘤内细胞因子施用/保留相结合的策略 患有黑色素瘤的狗，在UIUC兽医诊所。我们制定了一项战略， 注射细胞因子（特别是IL-2和IL-12），通过将它们表达为与天然的 胶原结合域。这种方法已被发现是安全的治疗在挑战 小鼠移植和GEM肿瘤模型，现在将进一步发展为更可靠的模型 用于人类癌症：自发性犬黑色素瘤。这些肿瘤是自发产生的， 远系繁殖群体，并在临床应用之前经历免疫编辑的自然进展。 演示文稿.犬黑色素瘤表现出与人黑色素瘤相似的病理生理学，包括 免疫浸润、排斥和沙漠亚型的存在。在目标1中，我们将利用 这些肿瘤的更真实的解剖结构，以优化肿瘤内的微药代动力学 给药，建立关于可注射体积分数的基本原则， 针头类型和部位数量。在目标2中，我们将测试治疗假设， 精确的时间程序化的强烈局部细胞因子刺激可以最佳地 与放射治疗相结合，以引发强烈的T细胞疫苗应答， 对疗效的系统性影响。在目标3中，我们将在犬中进行临床试验 黑色素瘤严格比较肿瘤内细胞因子治疗的替代剂量方案 辐照后。我们假设，细胞因子注射前的时间延迟将导致 对结果有着至关重要的影响这种学科间的合作已经开始， 和令人兴奋的初步治疗数据。 该项目的总体目标是开发改进的人类癌症免疫疗法 将联合收割机肿瘤内免疫治疗与局部放疗相结合的方案。多个先前 该领域的临床试验尚未实现这种方法的全部承诺，但通过执行 快速设计-构建-测试-学习周期在自发性犬黑色素瘤中，我们希望能够汇聚 更有效的策略。

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.