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.

项目总结/摘要 尽管免疫疗法，特别是PD-1/PD-L1抑制剂的免疫检查点抑制（ICI）， 随着越来越多的突破性进展，成为癌症治疗的第四大支柱， 成功考虑到它们能够以最小的细胞毒性对异质性肿瘤细胞迅速发挥其细胞毒性作用， 在不良事件中，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，特别是对于实体瘤，需要创新的方法来成功地 将新型NK免疫治疗方法转化为临床。患有癌症的狗是一个很好的方法来评估 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， 包括在免疫系统完整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，拟议的项目将测试一种创新的同种异体NK治疗方法， 过继转移与我们的比较研究开发的新型犬源化抗PD-L1抗体组合， 肿瘤组使用共同临床II期试验形式，将治疗患有局部晚期黑色素瘤的犬 放射治疗（RT），过继转移来自健康比格犬的扩增/活化的同种异体NK细胞 供体，并使用我们的狗抗PD-L1抗体进行免疫检查点阻断。作为第一个使用NK细胞的试验， 在临床环境中，转移联合ICI治疗自发性肿瘤，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，并将评估未来先行者的障碍。 实体瘤的人体试验由于已知NK细胞活性由PD-1/PD-L1轴介导， 作为一个关键的抑制性NK标记物，拟议的研究将提供关键的洞察力的潜在机制， 克服导致单独使用NK细胞免疫疗法的反应不显著的NK功能障碍。 此外，RT是不可切除的恶性肿瘤的标准治疗的一部分，并已被证明具有 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 作为犬临床试验的领导者，以及它们作为工具来执行NK细胞的多维分析。 类似地，这种新型免疫肿瘤学（IO）疗法的潜在高影响将通过广泛的研究， 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， 评估细胞毒性变化的杀伤试验和表征差异基因表达的RNA测序 相关免疫群体的免疫力。虽然我们假设有意义的临床和免疫学效果， 尽管如此，我们仍将获得对狗作为未来狗的比较模型的关键见解， 人类IO研究。因此，除了可能产生重大的科学和临床影响外， 这项研究将为我提供比较癌症免疫疗法的尖端培训，为我准备一个 在癌症免疫学和NK免疫疗法方面，作为兽医科学家取得了成功。