Intratumoral Cytokine Immunotherapy Studies in Companion Canine Cancer Models

伴侣犬癌症模型中的瘤内细胞因子免疫治疗研究

• 批准号: 10609061
• 负责人: TIMOTHY M FAN
• 金额: $ 49.9万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-12 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609061
• 关键词: Abscopal effect; Address; Agonist; Anatomy; Animal Hospitals; Animals; Antigens; Area; Binding; Biological Assay; Biological Markers; Buffers; Cancer Model; Canis familiaris; Cell Death; Cells; Chimeric Proteins; Clinical; Clinical Trials; Collaborations; Collagen; Companions; Cytology; DNA Damage; Data; Diagnosis; Distant; Dose; Dyes; Enzymes; Epigenetic Process; Evaluation; Event; Exclusion; Exhibits; Extravasation; Fine needle aspiration biopsy; Flow Cytometry; Functional disorder; Future; Gene Expression; Generations; Genetic; Genetic Engineering; Guidelines; Heterogeneity; Human; Image; Immune; Immune system; Immunophenotyping; Immunotherapeutic agent; Immunotherapy; In Situ; Infiltration; Inflammatory; Injectable; Injections; Intention; Interferon Type II; Interleukin-1; Interleukin-12; Interleukin-2; Interleukin-6; Learning; Liquid substance; Malignant Neoplasms; Mechanics; Mediating; Metastatic Neoplasm to the Lung; Modeling; Monitor; Mus; Myeloid-derived suppressor cells; Needles; Neoplasm Transplantation; Oncology; Oral; Outcome; Patients; Pharmacodynamics; Placebos; Plasma; Population; Pre-Clinical Model; Probability; Process; Progression-Free Survivals; Property; Protein Engineering; Protocols documentation; Radiation; Radiation therapy; Regulatory T-Lymphocyte; Reporter; Research Personnel; Resected; Safety; Sampling; Schedule; Site; Solid Neoplasm; T-Lymphocyte; TNF gene; Techniques; Testing; Therapeutic; Therapeutic Effect; Therapeutic Index; Time; Transplantation; Treatment Protocols; Tumor Leakage; Tumor Volume; Tumor-infiltrating immune cells; Veterinary Medicine; anti-cancer; cancer immunotherapy; cancer therapy; clinical translation; combinatorial; companion animal; comparative; cytokine; cytokine therapy; design; design,build,test; draining lymph node; drug distribution; efficacy evaluation; experimental study; immune cell infiltrate; immune-related adverse events; improved; irradiation; lipophilicity; melanoma; mouse model; nano-string; neoplastic cell; novel; pharmacokinetics and pharmacodynamics; preclinical evaluation; primary endpoint; programs; rational design; recruit; retention rate; safety assessment; secondary endpoint; sound; standard of care; systemic toxicity; therapeutic evaluation; translation to humans; translational study; tumor; tumor progression; vaccine response

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.

项目概要 这是一项新的 MPI R01 提案，将蛋白质工程整合到免疫治疗中 （Wittrup，麻省理工学院）与比较肿瘤学/兽医学（Fan，UIUC）一起测试临床 在宠物中将放射治疗与瘤内细胞因子施用/保留相结合的策略 患有黑色素瘤的狗，在 UIUC 兽医诊所。我们制定了保留策略 通过将细胞因子（特别是 IL-2 和 IL-12）表达为与天然产物的融合物来原位注射细胞因子 胶原蛋白结合域。已发现这种方法可以安全地治愈挑战 小鼠移植和 GEM 肿瘤模型，现在将升级为更忠实的模型 用于人类癌症：自发性犬黑色素瘤。这些肿瘤自发产生于 远交种群，并在临床前经历免疫编辑的自然进展 推介会。犬黑色素瘤表现出与人类黑色素瘤相似的病理生理学，包括 免疫渗透、排除和沙漠亚型的存在。在目标 1 中，我们将利用 这些肿瘤的更真实的解剖学，以优化瘤内药物的微药代动力学 管理，建立有关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，我们将检验治疗假设： 精确时间编程的强烈局部细胞因子刺激可以得到最佳效果 与放射治疗相结合，以引发强烈的 T 细胞疫苗反应 随之而来的对疗效的系统性影响。在目标 3 中，我们将在犬类中进行临床试验 黑色素瘤严格比较瘤内细胞因子治疗的替代剂量安排 照射后。我们假设注射细胞因子之前的时间延迟将有一个 对结果具有关键的、全有或全无的影响。这种跨学科合作已经开始， 本文提供了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 将瘤内免疫治疗与局部放射相结合的方案。多个先前的 该领域的临床试验尚未实现这种方法的全部前景，但通过执行 自发性犬黑色素瘤的快速设计-构建-测试-学习周期，我们希望能够收敛 更有效地制定有效的策略。