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

基本信息

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
项目类别：
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

项目摘要

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.

免疫疗法的最新进展完全改变了治疗和提示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引入了治愈曾经几乎无法治疗的疾病的可能性。可悲的是，大多数具有转移性黑色素瘤的退伍军人仍将屈服于任务治疗，并增加效率的提高导致自身免疫并发症的风险增加。对于退伍军人到达检查点抑制的治疗限制很明显，需要新一代的免疫疗法。在这项建议，我们研究了一种完全不同的黑色素瘤免疫疗法方法。我们对此的愿景方法融合了癌症免疫学的许多长期和最新观察结果。众所周知传统的肿瘤疗法和现代免疫疗法都增强了对癌症;传统处理（如辐射或消融）通过破坏来放大肿瘤抗原表现肿瘤细胞和免疫疗法增强了肿瘤反应性T细胞的激活。肿瘤的表现抗原和反应性T细胞的激活在很大程度上是在肿瘤淋巴结中发生的癌症与免疫系统之间的接触线。在我们以前的优点评论中，我们了解到使用检查点抑制与自适应细胞转移产生A的联合方法进行免疫疗法质性地对黑色素瘤抗原的免疫力强。我们还表征了独特的肿瘤学肿瘤反应性记忆T细胞比传统效应T细胞具有适应性免疫疗法的优势。在最近的研究，我们了解到效应子和记忆T细胞的组合更加有效比单独的效应子或记忆T细胞。尽管他们对免疫疗法的理论有很大的承诺，但记忆T细胞的实际实用性是由于它们存在于少量数量中的事实。幸运的是，最近的一些观察已经开始阐明细胞代谢途径确定激活的T细胞是否将其分化为效应子或记忆T细胞；故意重定向途径可以将T细胞驱动到任何一种表型。有趣的是，有利于记忆的代谢条件 T细胞的发育本质上不利于癌细胞存活。同样重要的是，我们发现了一种用于隔离和扩展大量肿瘤反应效应子或记忆T细胞的技术从肿瘤淋巴结收获的淋巴细胞的细胞因子刺激。我们设想了黑色素瘤免疫疗法的新范式。在这种方法中，本地和系统使用检查点抑制作用，诸如辐射或肿瘤消融之类的Oncoamunologology疗法免疫疗法 - 不仅是为了治疗肿瘤，还可以放大肿瘤反应性T细胞的激活肿瘤淋巴结。接下来，局部注射携带T细胞的靶向调节剂的纳米颗粒代谢被吸收成肿瘤和周围淋巴细胞药 - 驱动抗癌作用，同时驱动抗癌作用激活的T细胞在肿瘤排出的淋巴结中针对记忆表型。患者接受次要手术体验这些肿瘤淋巴结及其淋巴细胞的程序，受到刺激和具有T细胞代谢的靶向调节剂的细胞因子刺激方案，产生大量和平行效应子和记忆黑色素瘤特异性T细胞的种群。这些单元被适当地转移进入患者，利用检查点抑制和自适应之间的合作益处免疫疗法。我们的范式着重于使用OncoMunological疗法的肿瘤淋巴结将癌症与免疫系统之间的前沿重新设计为最佳的天然发生器治疗和个性化T细胞。在此提案中，我们概述了一系列的鼠和人类实验这将确定下一代黑色素瘤免疫疗法的临床前有效性。