Enhancing natural killer immunotherapy with first-in-dog trials of inhaled recombinant IL-15 and super-agonist IL-15 in naturally occurring canine cancers

通过吸入重组 IL-15 和超级激动剂 IL-15 在自然发生的犬癌症中的首次犬试验，增强自然杀伤免疫治疗

• 批准号: 10247896
• 负责人: Robert J. Canter
• 金额: $ 54.05万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247896
• 关键词: Address; Adjuvant Chemotherapy; Adoptive Transfer; Advanced Malignant Neoplasm; Aftercare; Agonist; Amputation; Antigen-Antibody Complex; Antitumor Response; Aspirate substance; Attention; Autologous; Biological; Biological Assay; Biological Markers; Canis familiaris; Cells; Cellular immunotherapy; Clinical; Clinical Research; Clinical Trials; Combination immunotherapy; Companions; Cox Proportional Hazards Models; Data; Development; Diagnosis; Diagnostic radiologic examination; Disease; Dose; Dose-Limiting; Drug Kinetics; Expression Profiling; Failure; Flow Cytometry; Formulation; Gene Expression; Goals; Half-Life; Homing; Human; Immune; Immune Evasion; Immune system; Immunooncology; Immunosuppression; Immunotherapy; Inhalation; Injections; Interleukin-15; Investigational Therapies; Kinetics; Link; Lung; Malignant Neoplasms; Maximum Tolerated Dose; Mediating; Memory; Metastatic Melanoma; Metastatic Neoplasm to the Lung; Metastatic Osteosarcoma; Methods; Microscopic; Modality; Modeling; Molecular; Mutation; Natural Killer Cells; Neoplasm Metastasis; Nonmetastatic; Outcome; Patients; Play; Positron-Emission Tomography; Progression-Free Survivals; Recombinants; Regulatory T-Lymphocyte; Research; Resolution; Risk; Role; Safety; Serum; Site; Survival Rate; T memory cell; T-Lymphocyte; Testing; Time; Toxic effect; Translating; Translations; Tumor Tissue; Tumor-Infiltrating Lymphocytes; Work; antitumor effect; arm; cancer immunotherapy; cancer therapy; combat; companion animal; cytokine; design; exome sequencing; experience; immunotherapy trials; improved; in vivo; innovation; melanoma; mouse model; neoantigens; novel; novel strategies; osteosarcoma; outcome prediction; phase II trial; predicting response; primary endpoint; prospective; ranpirnase; response; response biomarker; risk benefit ratio; secondary endpoint; standard of care; subcutaneous; tool; transcriptome sequencing; tumor; tumor-immune system interactions

Project Summary This proposal seeks to build on our extensive preliminary data in canine immunotherapy trials to demonstrate that novel methods of exogenous cytokine delivery in combination with autologous natural killer (NK) cells in first-in-dog clinical trials represents a potentially high impact approach to optimize non-T cell based immunotherapies. This work is targeted to dogs with typically lethal, naturally occurring osteosarcoma (OSA) and melanoma, and the findings are expected to have important relevance for the design and translation of innovative immunotherapy approaches in humans. Inhaled (IH) IL-15 offers the advantages of local delivery of this immune-stimulatory cytokine, while limiting systemic exposure and thus potential toxicity. Super-agonist IL- 15 offers increased half-life and greater anti-tumor effects. Therefore, each of these cytokines is anticipated to alter the risk/benefit ratio in favor of their use. To accomplish these objectives, we propose the following three specific aims: 1) Targeting gross pulmonary metastases (OSA and melanoma) with first-in-dog delivery of inhaled (IH) human IL-15 and super-agonist IL-15; 2) Phase II trial of IH IL-15 and autologous NK cells to treat gross OSA and melanoma pulmonary metastases, and; 3) Targeting micro-metastatic disease using super- agonist IL-15 in primary OSA. The canine model represents a powerful tool in cancer immunotherapy research as an important link between murine models and human clinical studies. Dogs represent an attractive outbred combination of companion animals that experience spontaneous cancer development in the setting of an intact immune system. Importantly, these studies are designed to evaluate novel treatment combinations for advanced pulmonary metastases in the setting of gross disease, but also will determine the impact of this approach as first-line therapy when combined with standard-of-care treatments. Moreover, this work seeks to elucidate the cellular and molecular mechanisms that mediate an anti-tumor response (or non-response) in dogs with naturally occurring cancers. We will have the unique opportunity to perform whole exome sequencing and RNASeq on tumor tissue pre- and post-immunotherapy, and we will investigate whether a signature of mutational landscape and gene expression profiles can be developed to prospectively predict outcome and response to immune therapies. We will correlate these data to immunohistochemical, flow cytometry, and serum cytokine readouts for evidence of transition from “cold” to “hot” tumors predictive of favorable long term outcome. Hence, these canine trials and bio-marker studies represent an ideal strategy to inform and facilitate the rapid translation of novel, potentially high impact immune therapies to human patients with aggressive cancers.

项目概要 该提案旨在建立在我们在犬免疫治疗试验中的广泛初步数据的基础上，以证明 外源细胞因子与自体自然杀伤 (NK) 细胞相结合的新方法 首次在狗身上进行的临床试验代表了一种潜在的高影响力方法，用于优化基于非 T 细胞的药物 这项工作针对的是患有典型致命性自然骨肉瘤 (OSA) 的狗。 和黑色素瘤，预计这些发现将对设计和翻译具有重要意义 吸入 (IH) IL-15 具有局部递送的优势。 这种免疫刺激细胞因子，同时限制全身暴露，从而限制超级激动剂 IL- 的潜在毒性。 15 提供更长的半衰期和更强的抗肿瘤作用，因此，这些细胞因子中的每一种都有望发挥作用。 为了实现这些目标，我们提出以下三个建议。 具体目标： 1) 通过首次在犬体内给药来治疗肉眼肺转移（OSA 和黑色素瘤） 吸入（IH）人IL-15和超级激动剂IL-15；2）IH IL-15和自体NK细胞治疗的II期试验； 总体 OSA 和黑色素瘤肺转移；3) 使用超级靶向治疗微转移性疾病 原发性 OSA 中的激动剂 IL-15 犬模型代表了癌症免疫治疗研究的强大工具。 作为小鼠模型和人类临床研究之间的重要联系，狗代表了一种有吸引力的近交系。 在完整的环境中经历自发癌症发展的伴侣动物的组合 重要的是，这些研究旨在评估新的治疗组合。 晚期肺转移在肉眼疾病的情况下，也将决定这种影响 此外，这项工作旨在与标准护理治疗相结合作为一线治疗。 阐明介导抗肿瘤反应（或无反应）的细胞和分子机制 我们将有独特的机会对患有自然发生癌症的狗进行全外显子组检查。 对免疫治疗前后的肿瘤组织进行测序和 RNASeq，我们将研究是否 可以开发突变景观和基因表达谱的特征来前瞻性预测 我们将把这些数据与免疫组织化学、血流相关联。 细胞计数和血清细胞因子读数作为从“冷”肿瘤向“热”肿瘤转变的证据，可预测 因此，这些犬类试验和生物标志物研究代表了一种理想的策略。 为人类患者提供信息并促进新型、具有潜在高影响力的免疫疗法的快速转化 患有侵袭性癌症。