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

基本信息

批准号：
10445377
负责人：
TIMOTHY M FAN
金额：
$ 52.18万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
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/10445377
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 Exhibits Extravasation Fine needle aspiration biopsy Flow Cytometry Foundations 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 Techniques Testing Therapeutic Therapeutic Effect Therapeutic Index Time Translations Transplantation Treatment Protocols Tumor Leakage Tumor Volume Tumor-infiltrating immune cells Veterinary Medicine anti-cancer base cancer immunotherapy cancer therapy clinical translation combinatorial companion animal comparative cytokine cytokine therapy design design-build-test draining lymph node drug distribution experimental study 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 secondary endpoint sound standard of care systemic toxicity therapeutic evaluation translation to humans tumor tumor progression vaccine response

项目摘要

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。