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 尽管免疫疗法，尤其是对PD-1/PD-L1抑制剂的免疫检查点抑制（ICI），但已迅速 随着突破性进步的提高，成为癌症疗法的第四个支柱，仍然存在障碍 成功。鉴于它们能够快速对其对异质肿瘤细胞的细胞毒性作用的影响很小 不良事件，自然杀手（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反应ICI的患者。但是，缺乏一致 人类NK细胞试验中的反应，特别是对于实体瘤，需要创新方法成功 将新颖的NK免疫疗法转化为诊所。癌症的狗是评估的绝佳方法 新型免疫疗法是因为它们概括了人类癌的基本临床和遗传特征， 包括在完整的免疫系统环境下自发肿瘤的发展。加快翻译 在NK免疫疗法方法中，拟议的项目将测试同种异体NK的创新治疗 收养转移与我们比较开发的新型罐装抗PD-L1抗体相结合 肿瘤学小组。使用共同链接的II期试验格式，将治疗具有局部晚期黑色素瘤的狗 通过放射疗法（RT），从健康的小猎犬中扩张/激活的同种异体NK细胞的产物转移 使用我们的狗抗PD-L1抗体的供体和免疫检查点阻断。作为第一次使用NK单元的试验 在临床环境中自发性肿瘤上的ICI转移，本研究的结果将提供 对两种疗法机制的潜在变革性见解 对实体瘤的人类试验。由于已知NK细胞活性是由PD-1/PD-L1轴介导的PD-L1 作为关键的抑制性NK标记，拟议的研究将对潜在机制提供重要的见解 仅用NK细胞免疫疗法就可以克服NK功能障碍，从而导致不可思议的反应。 此外，RT是无法切除的恶性肿瘤的护理标准的一部分，已被证明具有 重要的免疫调节作用，包括肿瘤细胞对NK细胞毒性的敏化。坎特实验室是 犬临床试验的领导者以及它们用作对NK细胞进行多维分析的工具的使用。 同样，这种新型免疫肿瘤学（IO）疗法的潜在高影响将通过广泛研究 相关研究包括流式细胞仪，遵循供体和内源性NK细胞的区域差异， 杀死测定法评估细胞毒性的变化和RNA测序以表征差异基因表达 相关免疫种群。尽管我们假设有意义的临床和免疫学影响 但是，新型疗法，我们将获得对狗的关键见解，作为未来狗的比较模型和 人类IO研究。因此，除了产生重大科学和临床影响的潜力之外， 研究将为我提供比较癌症免疫疗法的尖端训练，以使我做好准备 作为癌症免疫学和NK免疫疗法的兽医科学家的成功职业。