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.

项目摘要/摘要 尽管免疫治疗，特别是使用PD-1/PD-L1抑制剂的免疫检查点抑制(ICI)迅速 成为癌症治疗的第四支柱，突破性进展日益增多，但仍存在障碍 成功。鉴于它们能够在极少量的情况下对异种肿瘤细胞迅速发挥细胞毒作用 不良事件，自然杀伤(NK)细胞已成为扩大癌症益处的有希望的工具 免疫疗法，包括那些从不开始或停止对ICI有反应的患者。然而，缺乏一致性 人类NK细胞试验的反应，特别是实体瘤，需要创新的方法才能成功 将新的自然杀伤细胞免疫疗法应用于临床。患癌症的狗是评估 新的免疫疗法，因为它们概括了人类癌症的基本临床和遗传特征， 包括在免疫系统完好的情况下发生自发性肿瘤。要加快翻译速度 在NK免疫治疗方法中，拟议的项目将测试同种异体NK的创新治疗 过继转移与我们比较研制的新型犬化抗PD-L1抗体相结合 肿瘤学小组。使用共同临床第二阶段试验模式，患有局部晚期黑色素瘤的狗将被治疗 在放射治疗(RT)下，过继转移健康比格犬扩增/激活的同种异体NK细胞 供体，免疫检查点封锁使用我们的狗抗PD-L1抗体。作为第一个使用NK细胞的试验 转移联合ICI治疗自发性肿瘤的临床研究结果将为 对这两种疗法的机制的潜在变革性见解，并将评估未来的First-in 实体肿瘤的人体试验。由于已知NK细胞活性是由PD-1/PD-L1轴与PD-L1共同介导的 作为一种关键的抑制性NK标志物，拟议的研究将提供关键的洞察潜在的机制 克服NK细胞功能障碍与单独使用NK细胞免疫疗法反应平淡有关。 此外，RT是不能切除的恶性肿瘤护理标准的一部分，并已被证明具有 重要的免疫调节作用，包括使肿瘤细胞对NK细胞毒性增敏。坎特实验室是 在犬类临床试验以及将其用作对NK细胞进行多维分析的工具方面处于领先地位。 同样，这种新的免疫肿瘤学(IO)疗法的潜在高影响将通过广泛的 包括流式细胞术在内的相关研究，以跟踪供者和内源性NK细胞的地区差异， 杀伤试验用于评估细胞毒性的变化，RNA测序用于表征差异基因表达 相关的免疫群体。尽管我们假设有意义的临床和免疫学影响 新的治疗方法，但我们仍将获得对狗的关键见解，作为未来狗和 人类IO研究。因此，除了可能产生重大的科学和临床影响外，完成这一 研究将为我提供比较癌症免疫疗法方面的尖端培训，为我准备 作为一名成功的兽医科学家，从事癌症免疫学和自然杀伤细胞免疫疗法。