Combining Radiation, Allogeneic Natural Killer Immunotherapy, and PD-L1 blockade in Dogs with Naturally-Occurring Melanoma

结合放疗、同种异体自然杀伤免疫疗法和 PD-L1 阻断治疗患有天然黑色素瘤的狗

• 批准号: 10679952
• 负责人: Aryana Razmara
• 金额: $ 4.03万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679952
• 关键词: Address; Adoptive Transfer; Adverse event; Allogenic; Antigen-Antibody Complex; Autologous; Biological Assay; Biopsy; Blood; CD8-Positive T-Lymphocytes; Cancer Model; Cancer Patient; Canis familiaris; Cells; Cellular immunotherapy; Clinic; Clinical; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Correlative Study; Data; Development; Disease; Dose; Effector Cell; Evaluation; Flow Cytometry; Functional disorder; Future; Gene Expression Profile; Genetic; Genomics; Goals; Granzyme; Homing; Human; Immune; Immune system; Immunologics; Immunooncology; Immunosuppression; Immunotherapy; Knowledge; Ligands; Lymphocyte; Lymphoma; Malignant Neoplasms; Mediating; Methods; Modeling; Modification; Mus; NK Cell Activation; NK cell therapy; Natural Killer Cell Immunotherapy; Natural Killer Cell toxicity; Natural Killer Cells; Neoplasm Metastasis; Oncologist; Oncology Group; Organ; PD-1/PD-L1; PD-L1 blockade; PDL1 inhibitors; Pathway interactions; Patients; Phase II Clinical Trials; Phenotype; Population; Pre-Clinical Model; Prognosis; Progression-Free Survivals; Radiation; Radiation therapy; Recording of previous events; Research; Residencies; Safety; Sampling; Scientist; Solid Neoplasm; Speed; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Time; Tissue-Specific Gene Expression; Tissues; Toxic effect; Training; Translating; Translations; Unresectable; Up-Regulation; Variant; anti-PD-L1 antibodies; cancer immunotherapy; cancer therapy; canine model; career; checkpoint inhibition; chimeric antigen receptor T cells; clinical effect; clinically relevant; companion animal; comparative; cytokine; cytotoxic; cytotoxicity; dimensional analysis; exhaustion; experience; first-in-human; genetic signature; immune checkpoint blockade; immunoregulation; improved; innovation; insight; lymph nodes; melanoma; mouse model; neoplastic cell; next generation; novel; novel therapeutics; osteosarcoma; palliative; phase II trial; pilot trial; predicting response; primary endpoint; programmed cell death ligand 1; regional difference; response; safety assessment; single cell sequencing; skills; species difference; standard of care; success; tool; trafficking; transcriptome; transcriptome sequencing; translational study; treatment response; tumor; tumor immunology; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Although immunotherapy, especially immune checkpoint inhibition (ICI) with PD-1/PD-L1 inhibitors, has rapidly become the fourth pillar in cancer therapy with increasing breakthrough advances, barriers still exist to its success. Given their ability to rapidly exert their cytotoxic effects on heterogeneous tumor cells with minimal adverse events, natural killer (NK) cells have emerged as promising tools to expand the benefits of cancer immunotherapy, including for patients who never start or stop responding to ICI. However, lack of consistent responses in human NK cell trials, especially for solid tumors, calls for innovative methods to successfully translate novel NK immunotherapy approaches to the clinic. Dogs with cancer are an excellent way to assess novel immunotherapies because they recapitulate fundamental clinical and genetic features of human cancers, including the development of spontaneous tumors in the setting of an intact immune system. To speed translation of NK immunotherapy approaches, the proposed project will test an innovative treatment of allogeneic NK adoptive transfer in combination with a novel caninized anti-PD-L1 antibody developed by our comparative oncology group. Using a co-clinical Phase II trial format, dogs with locally advanced melanoma will be treated with radiation therapy (RT), adoptive transfer of expanded/activated allogeneic NK cells from healthy beagle donors, and immune checkpoint blockade using our dog anti-PD-L1 antibody. As the first trial to use NK cell transfer in combination with ICI on spontaneous tumors in a clinical setting, the results of this study will provide potentially transformative insights into mechanisms of both therapies and will evaluate barriers for future first-in- human trials on solid tumors. Since NK cell activity is known to be mediated by the PD-1/PD-L1 axis with PD-L1 being a critical inhibitory NK marker, the proposed study will offer critical insight into potential mechanisms of overcoming NK dysfunction responsible for unimpressive responses with NK cell immunotherapies alone. Furthermore, RT is part of the standard of care for unresectable malignancies and has been shown to have important immunomodulatory effects, including sensitization of tumor cells to NK cytotoxicity. The Canter Lab is a leader in canine clinical trials as well as their use as tools to perform multidimensional analyses of NK cells. Similarly, the potentially high impact of this novel immuno-oncology (IO) therapy will be studied through extensive correlative studies including flow cytometry to follow the regional differences of donor and endogenous NK cells, killing assays to assess changes in cytotoxicity, and RNA sequencing to characterize differential gene expression of relevant immune populations. Although we hypothesize meaningful clinical and immunologic effects from this novel therapy, we will nevertheless gain key insights into the dog as a comparative model for future dog and human IO studies. Thus, beyond the potential for significant scientific and clinical impact, the completion of this study will provide me with cutting edge training in comparative cancer immunotherapy to prepare me for a successful career as a veterinary scientist in cancer immunology and NK immunotherapy.

项目概要/摘要 尽管免疫疗法，特别是使用 PD-1/PD-L1 抑制剂的免疫检查点抑制 (ICI)，已迅速 随着突破性进展成为癌症治疗的第四支柱，其障碍仍然存在 成功。鉴于它们能够以最小的成本快速对异质肿瘤细胞发挥细胞毒性作用 不良事件、自然杀伤 (NK) 细胞已成为扩大癌症益处的有前途的工具 免疫疗法，包括从未开始或停止对 ICI 做出反应的患者。然而，缺乏一致的 人类 NK 细胞试验（尤其是实体瘤试验）的反应需要创新方法来成功 将新型 NK 免疫治疗方法应用于临床。患有癌症的狗是一种很好的评估方法 新型免疫疗法，因为它们概括了人类癌症的基本临床和遗传特征， 包括在完整免疫系统的情况下自发性肿瘤的发展。加快翻译速度 NK 免疫治疗方法中，拟议项目将测试同种异体 NK 的创新治疗方法 过继转移与我们的比较公司开发的新型犬化抗 PD-L1 抗体相结合 肿瘤学组。使用联合临床 II 期试验形式，患有局部晚期黑色素瘤的狗将得到治疗 通过放射治疗 (RT)，从健康比格犬中继承扩增/激活的同种异体 NK 细胞 捐赠者，以及使用我们的狗抗 PD-L1 抗体进行免疫检查点封锁。作为首次尝试使用NK细胞 在临床环境中与 ICI 相结合对自发性肿瘤进行转移，本研究的结果将提供 对这两种疗法的机制具有潜在的变革性见解，并将评估未来首创的障碍 实体瘤人体试验。由于已知 NK 细胞活性是由 PD-1/PD-L1 轴与 PD-L1 介导的 作为一种关键的抑制性 NK 标记物，拟议的研究将为 NK 的潜在机制提供重要的见解。 克服单独使用 NK 细胞免疫疗法反应不佳的 NK 功能障碍。 此外，放疗是不可切除恶性肿瘤护理标准的一部分，并且已被证明具有 重要的免疫调节作用，包括肿瘤细胞对 NK 细胞毒性的敏感性。坎特实验室是 是犬类临床试验及其用作 NK 细胞多维分析工具的领导者。 同样，这种新型免疫肿瘤学 (IO) 疗法的潜在巨大影响将通过广泛的研究进行研究。 相关研究，包括流式细胞术，以追踪供体和内源性 NK 细胞的区域差异， 杀伤试验可评估细胞毒性的变化，RNA 测序可表征差异基因表达 相关免疫群体。尽管我们假设这会产生有意义的临床和免疫学影响 尽管是一种新颖的疗法，但我们仍将获得对狗的重要见解，作为未来狗的比较模型 人类 IO 研究。因此，除了具有重大科学和临床影响的潜力之外，这项研究的完成 研究将为我提供比较癌症免疫疗法的前沿培训，为我做好准备 作为癌症免疫学和 NK 免疫治疗领域的兽医科学家，他的职业生涯很成功。