Re-engineering the tumor draining lymph node to achieve memory T cell-based adoptive immunotherapy

重新设计肿瘤引流淋巴结以实现基于记忆 T 细胞的过继免疫治疗

• 批准号: 10049957
• 负责人: Clifford Cho
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10049957
• 关键词: Ablation; Adoptive Cell Transfers; Adoptive Immunotherapy; Antigen Presentation; Antigenic Specificity; Antigens; Autoimmune; Automobile Driving; Back; Biological; CD8-Positive T-Lymphocytes; Cell Differentiation Inhibition; Cell Proliferation; Cell Separation; Cell Survival; Cells; Cellular Metabolic Process; Clinical; Clinical Trials; Disabled Persons; Disease; Engineering; Exposure to; Foundations; Generations; Goals; Human; IL7 gene; Immune; Immune response; Immune system; Immunity; Immunotherapy; In Vitro; Infusion procedures; Injections; Interleukin-15; Interleukin-2; Intervention; Laboratories; Laboratory Research; Light; Longevity; Lymphatic; Lymphocyte; Lymphocyte Activation; Lymphocyte Harvest; Malignant Neoplasms; Memory; Metabolic; Metabolic Pathway; Metabolism; Metastatic Melanoma; Methodology; Methods; Minor Surgical Procedures; Modernization; Mus; Output; Pathway interactions; Patients; Phenotype; Population; Prognosis; Protocols documentation; Radiation; Radiation therapy; Research; Resected; Risk; Series; Signal Pathway; Source; Splenocyte; T cell differentiation; T cell therapy; T memory cell; T-Cell Development; T-Lymphocyte; Techniques; Therapeutic; Tumor Antigens; Tumor Expansion; Tumor-Infiltrating Lymphocytes; Validation; Veterans; Vision; Work; anti-CTLA4; anti-PD1 antibodies; anti-cancer; anti-tumor immune response; antitumor effect; base; cancer care; cancer cell; cancer immunotherapy; checkpoint inhibition; combinatorial; conventional therapy; cytokine; draining lymph node; effector T cell; efficacy validation; experimental study; fascinate; in vivo; lymph nodes; melanoma; nanoparticle; neoplastic cell; next generation; novel strategies; personalized approach; pre-clinical; preconditioning; prevent; tumor; tumor ablation; tumor immunology; tumor specificity

Recent advances in immunotherapy have completely transformed the treatment and prognosis of veterans with advanced melanoma. Checkpoint inhibition immunotherapy using anti-CTLA-4 and anti-PD-1 antibodies has introduced the possibility of cure for a disease that was once practically untreatable. Sadly, the majority of veterans with metastatic melanoma will still succumb despite treatment, and incremental improvements in efficacy have brought increasing risks of autoimmune complications. For veterans reaching the therapeutic limits of checkpoint inhibition, it is clear that a new generation of immunotherapy is needed. In this proposal, we examine an entirely different approach to melanoma immunotherapy. Our vision for this approach fuses a number of long-standing and recent observations in cancer immunology. It is well known that conventional oncological therapy and modern immunotherapy both heighten the immune response to cancer; conventional treatments like radiation or ablation magnify tumor antigen presentation by destroying tumor cells, and immunotherapy potentiates the activation of tumor-reactive T cells. The presentation of tumor antigens and the activation of reactive T cells occur, in large part, in the tumor-draining lymph node – the front line of contact between cancer and the immune system. In our previous Merit Review, we learned that a combinatorial approach to immunotherapy using checkpoint inhibition with adoptive cell transfer generated a qualitatively stronger immunity to melanoma antigen. We also characterized the unique oncological advantages of tumor-reactive memory T cells over traditional effector T cells for adoptive immunotherapy. In recent studies, we have learned that the combination of effector and memory T cells is strikingly more effective than effector or memory T cells alone. Despite their enormous theoretical promise for immunotherapy, the practical utility of memory T cells is handicapped by the fact that they exist in vanishingly small quantities. Fortunately, some very recent observations have begun to shed light on the cellular metabolic pathways that determine whether activated T cells differentiate into effector or memory T cells; intentional redirection of these pathways can drive T cells toward either phenotype. Interestingly, the metabolic conditions that favor memory T cell development are inherently unfavorable for cancer cell survival. Just as importantly, we have discovered a technique for isolating and expanding large quantities of tumor-reactive effector or memory T cells using cytokine stimulation of lymphocytes harvested from tumor-draining lymph nodes. We envision a new paradigm of melanoma immunotherapy. In this approach, local and systemic oncoimmunological therapies like radiation or tumoral ablation are used with checkpoint inhibition immunotherapy – not simply to treat tumors, but to also magnify the activation of tumor-reactive T cells within tumor-draining lymph nodes. Next, local injection of nanoparticles carrying targeted modulators of T cell metabolism are taken up into tumors and peritumoral lymphatics – exerting anti-cancer effects, while driving activated T cells in tumor-draining lymph nodes toward memory phenotype. Patients undergo a minor surgical procedure to excise these tumor-draining lymph nodes, and their lymphocytes are subjected to stimulation and cytokine stimulation protocols with targeted modulators of T cell metabolism to generate massive and parallel populations of effector and memory melanoma-specific T cells. These cells are adoptively transferred back into the patient, taking advantage of the cooperative benefits between checkpoint inhibition and adoptive immunotherapy. Our paradigm focuses on the tumor-draining lymph node, using oncoimmunological therapies to re-engineer this leading edge between cancer and the immune system into a natural generator of optimally therapeutic and personalized T cells. In this proposal, we outline a series of murine and human experiments that will establish the preclinical validity of this next generation of melanoma immunotherapy.

免疫治疗的最新进展已经完全改变了 患有晚期黑色素瘤的退伍军人使用抗CTLA-4和抗PD-1的检查点抑制免疫疗法 抗体为一种曾经几乎无法治愈的疾病带来了治愈的可能性。可惜 大多数患有转移性黑色素瘤的退伍军人尽管接受了治疗， 功效的提高带来了自身免疫并发症的增加的风险。对于退伍军人， 检查点抑制的治疗极限，很明显，需要新一代的免疫疗法。在 在这个提议中，我们研究了一种完全不同的黑色素瘤免疫治疗方法。我们对此的愿景 这种方法融合了癌症免疫学中许多长期和最近的观察结果。众所周知的是 传统的肿瘤治疗和现代免疫治疗都能增强免疫反应， 癌症;传统的治疗，如放射或消融，通过破坏 肿瘤细胞，并且免疫疗法增强肿瘤反应性T细胞的活化。肿瘤的表现 抗原和反应性T细胞的活化在很大程度上发生在肿瘤引流淋巴结--肿瘤的前部， 癌症和免疫系统之间的接触线。在我们之前的Merit Review中，我们了解到 使用检查点抑制与过继细胞转移的免疫疗法的组合方法产生了一种新的免疫疗法， 对黑色素瘤抗原有更强的免疫力。我们还描述了独特的肿瘤学特征， 肿瘤反应性记忆T细胞在过继免疫治疗中优于传统效应T细胞。在 最近的研究表明，效应T细胞和记忆T细胞的结合， 比单独的效应或记忆T细胞更有效。尽管它们在理论上对免疫疗法有着巨大的希望， 记忆性T细胞的实际应用受到其存在量少得几乎不可见的事实的阻碍。 幸运的是，最近的一些观察已经开始揭示细胞代谢途径， 确定活化的T细胞是否分化为效应T细胞或记忆T细胞;这些细胞的有意重定向 信号通路可以驱使T细胞趋向任一种表型。有趣的是，有利于记忆的代谢条件 T细胞发育本质上不利于癌细胞存活。同样重要的是，我们发现 分离和扩增大量肿瘤反应性效应或记忆T细胞的技术， 从肿瘤引流淋巴结收集的淋巴细胞的细胞因子刺激。 我们设想了一种新的黑色素瘤免疫治疗模式。在这种方法中，地方和系统 肿瘤免疫疗法如放射或肿瘤消融与检查点抑制一起使用 免疫疗法-不仅要治疗肿瘤，而且要放大肿瘤内肿瘤反应性T细胞的激活。 肿瘤引流淋巴结接下来，局部注射携带靶向T细胞调节剂的纳米颗粒， 代谢被吸收到肿瘤和瘤周组织中-发挥抗癌作用， 肿瘤引流淋巴结中的活化T细胞朝向记忆表型。患者接受小手术 手术切除这些肿瘤引流淋巴结，并且它们的淋巴细胞受到刺激， 使用靶向T细胞代谢调节剂的细胞因子刺激方案，以产生大量和平行的 效应和记忆黑素瘤特异性T细胞群。这些细胞被过继性地转移回 利用检查点抑制和过继性免疫抑制之间的协同效益， 免疫疗法。我们的范例集中在肿瘤引流淋巴结，使用肿瘤免疫疗法 重新设计癌症和免疫系统之间的这种领先优势，使其成为一种最佳的天然发电机， 治疗性和个性化的T细胞。在这个提议中，我们概述了一系列小鼠和人类实验 这将确立下一代黑色素瘤免疫疗法的临床前有效性。