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：
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
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/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

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.

项目摘要这是一个新的MPI R01提案，将蛋白质工程汇总为免疫疗法（MIT Wittrup）与比较肿瘤学/兽医医学（FAN，UIUC）测试临床将放疗与肿瘤内细胞因子给药/保留pET相结合的策略在UIUC兽医诊所，有黑色素瘤的狗。我们已经制定了保留的策略原位注入细胞因子（尤其是IL-2和IL-12），通过表达为自然的融合胶原结合域。已经发现这种方法在挑战方面可以安全地治愈鼠类移植和宝石肿瘤模型，现在将成为一个更忠实的模型对于人类癌症：自发的犬黑色素瘤。这些肿瘤自发出现杂种种群，并在临床之前进行自然的免疫程序进展推介会。犬黑色素瘤表现出类似于人类黑色素瘤的病理生理学，包括免疫浸润，排除和沙漠亚型的存在。在AIM 1中，我们将利用这些肿瘤的更现实的解剖结构，以优化肿瘤内的微药物管理，建立有关注射体积分数的基础原理，针类型和站点数量。在AIM 2中，我们将检验以下治疗假设精确编程的激烈局部细胞因子刺激可以是最佳的结合放射疗法，以使强烈的T细胞疫苗接种反应与因此对疗效的系统影响。在AIM 3中，我们将在犬类中进行临床试验黑色素瘤严格比较肿瘤内细胞因子疗法的替代剂量调度辐照后。我们假设细胞因子注射之前的时间延迟将具有对结果的关键，无所不包的影响。这种学科的合作已经开始本文介绍了令人兴奋的初步治疗数据。该项目的总体目的是开发改善的人类癌症免疫疗法将肿瘤内免疫疗法与局部放射线相结合的方案。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，但要执行自发犬黑色素瘤中的快速设计建造测试循环，我们希望收敛更有效地采用有效的策略。