Preclinical Optimization of Melanoma Adoptive T Cell Immunotherapy

黑色素瘤过继性 T 细胞免疫疗法的临床前优化

• 批准号: 8764622
• 负责人: Clifford Cho
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 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 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764622
• 关键词: Acute; Adoptive Immunotherapy; Adoptive Transfer; Affect; Animal Model; Antigen Presentation; Antigens; Apoptosis; Apoptotic; Biological; Biological Assay; Cell Death; Cells; Clinical; Clinical Trials; Development; Educational process of instructing; Exposure to; Harvest; Homeostasis; Human; Immune; Immune response; Immune system; Immunity; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Infiltration; Interleukin-15; Interleukin-7; Investigation; Laboratories; Learning; Life; Light; Lymphocyte; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Memory; Modeling; Patients; Phase; Phenotype; Population; Predisposition; Proliferating; Protocols documentation; Resistance; Rest; Series; Staging; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Thermal Ablation Therapy; Toxic effect; Translating; Tumor Antigens; Tumor Immunity; Up-Regulation; Veterans; Work; base; cancer therapy; conventional therapy; cytokine; design; expectation; experience; fighting; human subject; improved; in vitro Model; in vivo; interest; melanoma; neoplastic cell; novel; pre-clinical; prevent; public health relevance; research study; response; success; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Immunotherapeutic strategies to orient the immune system against tumor cells continue to hold great promise for patients with advanced melanoma. The paucity of conventional treatment options and the complexity and inconsistency of clinical immunotherapy have motivated the development of scientific models to identify ways to improve immunotherapy. Thus far, these models have employed melanoma-specific T cell populations that have been activated and expanded ex vivo for adoptive transfer into lymphodepleted hosts bearing melanoma tumors. Although designed to mimic paradigms of experimental adoptive immunotherapy used in human subjects, the complexity of these models has obfuscated our ability to precisely characterize the in vivo interaction that takes place between adoptively transferred melanoma-specific T cells and melanoma tumors. Our laboratory has developed a simple quantitative animal model of melanoma-induced T cell suppression to demonstrate that in vivo exposure to growing melanoma tumors weakens the ability of T cells to undergo antigen-driven proliferative expansion by heightening their susceptibility to apoptotic cell death. This alteration of T cell responsiveness fundamentally reshapes the entire spectrum of activated T cell homeostasis with one interesting exception: memory T cells appear to be uniquely resistant to this melanoma- induced suppression. In this proposal, we have drawn on our previous experience to introduce new, simplified models of melanoma adoptive T cell immunotherapy to test a central hypothesis: that the efficacy of melanoma adoptive immunotherapy can be optimized with the use of memory T cells. In the first series of experiments, we will test a first subhypothesis: that the in vivo durability of adoptively transferred melanoma-specific T cells is impaired by melanoma-induced upregulation of T cell apoptosis. We will examine the fate of adoptively transferred T cell populations in vivo to characterize how melanoma influences the ability of therapeutic populations of melanoma-specific T cells to persist. In the next series of experiments, we will test a second subhypothesis: that memory T cells are optimal mediators of melanoma adoptive immunotherapy because of an enhanced ability to survive and target melanoma antigens following adoptive transfer. We will compare the in vivo persistence of adoptively transferred melanoma-specific T cells in various stages of maturation (resting T cells, acute effector T cells, unsorted memory T cells, central memory T cells, and effector memory T cells) following adoptive transfer, as well as their abilities to infiltrate melanoma tumors, induc tumoral regression, and promote tumoral immunity. From there, we will test a third subhypothesis: that adoptive immunotherapy is more effective when endogenous melanoma-specific T cell responses are preserved. We will employ highly quantitative assays used in our laboratory to determine how endogenous melanoma-specific T cell responses are affected by adoptive immunotherapy, and will determine if therapeutic efforts to preserve and enhance those endogenous responses promote the efficacy of adoptive immunotherapy. In the fourth and final series of experiments, we will test a fourth subhypothesis: that melanoma-specific memory T cells can be harvested and expanded to quantities that will permit the clinical realization of memory T cell-based adoptive immunotherapy. Here, we will examine human melanoma tumors to verify that the biological advantages of memory T cells can be put to clinical use. This final piece will enable us to begin the next phase of investigation: a clinical rial to introduce a novel and critical form of cancer treatment. In summary, we are proposing a series of experiments with which the biological underpinnings of adoptive T cell immunotherapy may be rationally and critically explored. It is our expectation that this work will allow us to fuly actualize the enormous potential of this desperately needed treatment for veterans afflicted with melanoma. PUBLIC HEALTH RELEVANCE: The incidence of melanoma is increasing faster than that of any other cancer; yet the few treatment options currently available for Veterans with advanced melanoma offer enormous toxicity with minimal-to-no clinical benefit. Experimental efforts to fight melanoma using the patient's own immune system have yielded intriguing but preliminary successes. Our laboratory has developed an experimental way to dissect the biological underpinnings of immunotherapy. We outline a series of experiments that will teach us (1) how melanoma tumors affect the ability of melanoma-specific to persist following adoptive transfer, (2) which immune cells would be most effective in mediating immunotherapy, (3) how current forms of melanoma treatment may synergize with immunotherapy to maximize clinical benefit, and (4) ways to translate these findings into human studies. In short, we will learn ways in which the enormous promise of melanoma immunotherapy may be actualized.

描述（由申请人提供）： 引导免疫系统对抗肿瘤细胞的免疫治疗策略继续为晚期黑色素瘤患者带来巨大希望。常规治疗方案的缺乏以及临床免疫治疗的复杂性和不一致性促使科学模型的发展，以确定改进免疫治疗的方法。到目前为止，这些模型已经采用了黑色素瘤特异性 T 细胞群，这些细胞群已被激活并在体外扩增，用于过继转移到携带黑色素瘤的淋巴耗竭宿主中。尽管这些模型旨在模仿用于人类受试者的实验性过继免疫疗法的范式，但这些模型的复杂性使我们无法精确表征过继转移的黑色素瘤特异性 T 细胞和黑色素瘤肿瘤之间发生的体内相互作用。我们的实验室开发了一种简单的黑色素瘤诱导 T 细胞抑制的定量动物模型，以证明体内暴露于生长中的黑色素瘤肿瘤会增强 T 细胞对凋亡细胞死亡的敏感性，从而削弱 T 细胞进行抗原驱动的增殖扩张的能力。 T 细胞反应性的这种改变从根本上重塑了活化 T 细胞稳态的整个范围，但有一个有趣的例外：记忆 T 细胞似乎对这种黑色素瘤诱导的抑制具有独特的抵抗力。在本提案中，我们借鉴了以往的经验，引入了新的、简化的黑色素瘤过继性 T 细胞免疫治疗模型，以测试一个中心假设：黑色素瘤过继性免疫治疗的疗效可以通过使用记忆 T 细胞来优化。在第一个系列的实验中，我们将测试第一个子假设： 过继转移的黑色素瘤特异性 T 细胞的体内耐久性会因黑色素瘤诱导的 T 细胞凋亡上调而受到损害。我们将检查体内过继转移的 T 细胞群的命运，以表征黑色素瘤如何影响黑色素瘤特异性 T 细胞治疗群体持续存在的能力。在接下来的一系列实验中，我们将测试第二个子假设：记忆 T 细胞是黑色素瘤过继免疫治疗的最佳介质，因为在过继转移后，记忆 T 细胞的生存能力和靶向黑色素瘤抗原的能力增强。我们将比较过继转移后不同成熟阶段的过继转移黑色素瘤特异性 T 细胞（静息 T 细胞、急性效应 T 细胞、未分类记忆 T 细胞、中央记忆 T 细胞和效应记忆 T 细胞）的体内持久性，以及它们浸润黑色素瘤、诱导肿瘤消退和促进肿瘤免疫的能力。从这里开始，我们将测试第三个子假设：当内源性黑色素瘤特异性 T 细胞反应得以保留时，过继免疫疗法会更有效。我们将采用实验室中使用的高度定量测定来确定过继性免疫疗法如何影响内源性黑色素瘤特异性 T 细胞反应，并将确定维持和增强这些内源性反应的治疗努力是否会促进过继性免疫疗法的疗效。在第四个也是最后一个系列的实验中，我们将测试第四个子假设：可以收获黑色素瘤特异性记忆 T 细胞并将其扩大到允许临床实现基于记忆 T 细胞的过继免疫疗法的数量。在这里，我们将检查人类黑色素瘤肿瘤，以验证记忆T细胞的生物学优势可以应用于临床。这最后一篇文章将使我们能够开始下一阶段的研究：一项临床试验，以介绍一种新颖且重要的癌症治疗形式。总之，我们提出了一系列实验，可以合理且批判性地探索过继性 T 细胞免疫疗法的生物学基础。我们期望这项工作能够让我们充分认识到这种对患有黑色素瘤的退伍军人来说急需的治疗方法的巨大潜力。 公共卫生相关性： 黑色素瘤的发病率增长速度快于任何其他癌症；然而，目前可用于患有晚期黑色素瘤的退伍军人的少数治疗方案具有巨大的毒性，而临床益处却很小甚至没有。利用患者自身免疫系统对抗黑色素瘤的实验努力已经取得了有趣但初步的成功。我们的实验室开发了一种实验方法来剖析免疫疗法的生物学基础。我们概述了一系列实验，这些实验将告诉我们（1）黑色素瘤肿瘤如何影响黑色素瘤特异性在过继转移后持续存在的能力，（2）哪些免疫细胞在介导免疫治疗方面最有效，（3）目前的形式如何黑色素瘤治疗可能与免疫疗法协同作用，以最大限度地提高临床效益，以及（4）将这些发现转化为人体研究的方法。简而言之，我们将了解如何实现黑色素瘤免疫疗法的巨大前景。