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: 8435605
• 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/8435605
• 关键词: Ablation; 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; 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）： 针对肿瘤细胞的免疫系统定向的免疫治疗策略继续对晚期黑色素瘤患者保持巨大的希望。常规治疗方案的匮乏以及临床免疫疗法的复杂性和不一致性促进了科学模型的发展，以确定改善免疫疗法的方法。到目前为止，这些模型采用了黑色素瘤特异性的T细胞群体，这些细胞群已被激活并扩展了离体，以使其转移到具有黑色素瘤肿瘤的淋巴结障碍宿主中。尽管设计用于模仿人类受试者使用的实验性收养免疫疗法的范例，但这些模型的复杂性使我们精确地表征了我们精确地表征在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的能力。我们的实验室已经开发了一种简单的黑色素瘤诱导T细胞抑制的动物模型，以证明体内暴露于生长的黑色素瘤肿瘤可通过增强其对凋亡细胞死亡的易感性来增强其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的T细胞稳态的整个频谱，并具有一个有趣的例外：记忆T细胞似乎对这种黑色素瘤诱导的抑制具有独特的抗性。在此提案中，我们借鉴了以前的经验，这些经验引入了黑色素瘤过继的T细胞免疫疗法的新型，简化的模型来检验中心假设：使用记忆T细胞，可以通过使用记忆T细胞来优化黑色素瘤过养免疫疗法的功效。在第一个系列实验中，我们将测试第一个亚物种： 黑色素瘤诱导的T细胞凋亡的上调会损害采用转移的黑色素瘤特异性T细胞的体内耐用性。我们将研究体内传递转移的T细胞群体的命运，以表征黑色素瘤如何影响黑色素瘤特异性T细胞持续存在治疗群体的能力。在下一系列实验中，我们将测试第二个亚物种：记忆T细胞是黑色素瘤过养免疫疗法的最佳介质，因为生存的能力增强和靶向靶向黑色素瘤抗原后传递后转移。我们将比较在产物转移后的各种成熟阶段（静止的T细胞，急性效应T细胞，未分离的记忆T细胞，中心记忆T细胞和效应记忆T细胞），在产生的T细胞，急性效应T细胞，无效的记忆T细胞和效应的记忆T细胞）中比较了体内持久性。从那里开始，我们将测试第三个亚物种：当保留内源性黑色素瘤特异性T细胞反应时，收养免疫疗法更有效。我们将在实验室中使用高度定量的测定方法来确定内源性黑色素瘤特异性T细胞反应如何受收养免疫疗法的影响，并将确定是否保留和增强这些内源性反应的治疗努力促进了收养免疫疗法的功效。在第四个也是最后一系列的实验中，我们将测试第四个亚物种：黑色素瘤特异性的记忆T细胞可以收获并扩展到数量，以允许基于记忆T细胞的临床实现基于记忆T细胞的产物免疫疗法。在这里，我们将检查人黑色素瘤肿瘤，以验证记忆T细胞的生物学优势可以临床使用。这最后一件作品将使我们能够开始下一阶段的调查：一种临床上，引入了一种新颖而关键的癌症治疗形式。总而言之，我们提出了一系列实验，该实验可以通过理性和批判性地探索过收养T细胞免疫疗法的生物基础。我们期望这项工作将使我们能够实现这种迫切需要治疗的巨大潜力，以使患有黑色素瘤折磨的退伍军人。 公共卫生相关性： 黑色素瘤的发病率比任何其他癌症的发病率更快。然而，目前为患有晚期黑色素瘤的退伍军人提供的少数治疗方案提供了巨大的毒性，并且最小的临床益处。使用患者自己的免疫系统与黑色素瘤作斗争的实验性努力取得了有趣但初步的成功。我们的实验室已经开发了一种实验方法来剖析免疫疗法的生物基础。我们概述了一系列实验，这些实验将教会我们（1）黑色素瘤肿瘤如何影响黑色素瘤特异性在收养转移后持续存在的能力，（2）免疫细胞在介导免疫疗法方面最有效，（3）当前的黑色素瘤治疗方式如何通过免疫疗法进行免疫疗法来使临床受益最大化的临床益处和（4）变化为人类研究，并将其转化为人类研究。简而言之，我们将学习可能实现黑色素瘤免疫疗法的巨大希望。