Gamma Delta T Cells--Immunotherapy for Melanoma

Gamma Delta T 细胞——黑色素瘤的免疫疗法

• 批准号: 6704765
• 负责人: RICHARD D LOPEZ
• 金额: $ 23.86万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6704765
• 关键词: CD2 molecule; T lymphocyte; apoptosis; human subject; human therapy evaluation; interleukin 12; interleukin 15; leukocyte activation /transformation; melanoma; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; passive immunization; patient oriented research; vaccine development

DESCRIPTION (provided by the applicant): In vitro, the mitogenic stimulation of human T-lymphocytes usually favors the proliferation of gamma/delta-T cells but can often induce apoptosis in gamma/delta-T cells, thus preventing their expansion. We have identified a CD2-mediated, interleukin (IL)-12-dependent signaling pathway which inhibits apoptosis in mitogen-stimulated human gamma/delta-T cells. Biologically, these findings are significant as they may contribute to a greater understanding of how this or similar signaling pathways serve to maintain or regulate the gamma/delta-T cell compartment in vivo. Moreover, these findings have an important practical significance: By exploiting this signaling pathway, our laboratory has been able to develop the methodologies permitting the large-scale in vitro expansion of viable, apoptosis-resistant human gamma/delta-T cells, an undertaking until now, not possible. As importantly, these apoptosis-resistant gamma/delta-T cells (now readily obtainable) can be shown to mediate significant innate, major histocompatibility complex (MHC)-unrestricted cytotoxicity against a variety of human tumor cell lines in vitro, including melanoma cell lines which were found to be exquisitely sensitive to cytolysis mediated by apoptosis-resistant gamma/delta-T cells, but not control alpha/beta-T cells. In this grant, two distinct, yet related questions regarding apoptosis-resistant gamma/delta-T cells will be addressed: 1) What are the biological mechanisms underlying the enhanced expansion and survival of apoptosis-resistant gamma/delta-T cells? and, 2) How might we begin to exploit for direct clinical benefit the intrinsic or innate antitumor properties displayed by apoptosis-resistant gamma/delta-T cells? The first question can be restated as our testable overall hypothesis which is that: CD2-mediated, IL-12-dependent signaling is a mechanism by which human gamma/delta-T cells can acquire resistance to apoptosis and that this pathway is an important determinant in the regulation of the survival (and therefore, function) of gamma/delta-T cells. This basic question will be addressed primarily in Specific Aim 1 where we propose to examine the molecular and cellular consequences of CD2-mediated, IL-12-dependent signaling in human gamma/delta-T cells with respect to inhibition of apoptosis. The second question relates to a corollary to our overall hypothesis which is that: Apoptosis-resistant gamma/delta-T cells which readily expand in culture - yet retain intrinsic or innate MHC-unrestricted antitumor cytotoxicity - can provide an important means to examine both the pre-clinical biology and the direct clinical potential of apoptosis-resistant human gamma/delta-T cells as a new form of adoptive cellular immunotherapy for melanoma. This question will be addressed in Specific Aim 2 and Specific Aim 3 where we will define the biology of the antitumor cytotoxicity mediated by apoptosis-resistant gamma/delta-T cells against human melanoma cells. A key feature to these studies is that we will examine the innate antitumor activity of apoptosis-resistant gamma/delta-T cells derived from both normal individuals and from patients with melanoma. Ultimately, we will directly determine whether melanoma-reactive apoptosis-resistant gamma/delta-T cells can be identified and propagated in vitro from both peripheral blood and from primary tumor samples (gamma/delta-T cell tumor-infiltrating lymphocytes, or TIL) obtained from patients with melanoma. These findings may provide the basis for the rational design of future immunotherapy trials for the treatment of melanoma or other malignancies.

描述（由申请人提供）：在体外，有丝分裂刺激 人类T淋巴细胞通常有利于γ/delta-t细胞的增殖，但 通常会诱导γ/delta-T细胞中的凋亡，从而阻止其 扩张。我们已经确定了CD2介导的白介素（IL）-12依赖性 信号通路，抑制有丝分裂原刺激的人的凋亡 γ/delta-T细胞。从生物学上讲，这些发现很重要，因为它们可能 有助于更深入地了解这种或类似的信号通路 在体内维持或调节γ/delta-t细胞室。 此外，这些发现具有重要的实际意义： 利用此信号通路，我们的实验室能够开发 方法学允许大规模的活体扩张， 抗凋亡的人伽玛/delta-T细胞，直到现在的事业，而不是 可能的。重要的是，这些耐凋亡的伽马/delta-t细胞（现在 可以显示）可以证明可以调节重要的先天，主要 组织相容性复合物（MHC） - 无限制的细胞毒性，针对多种 体外人类肿瘤细胞系，包括发现的黑色素瘤细胞系 对抗细胞凋亡介导的细胞溶解非常敏感 γ/delta-T细胞，但不能控制α/β-T细胞。在这笔赠款中，两个 关于抗凋亡的伽马/delta-t的独特但相关的问题 细胞将被解决：1） 增强了抗细胞凋亡的γ/delta-T细胞的膨胀和存活？ 2）我们将如何开始利用直接临床益处 或由抗凋亡的伽马/delta-t显示的先天抗肿瘤特性 细胞？第一个问题可以作为我们可检验的总体假设来重述 就是这样：CD2介导的IL-12依赖性信号传导是一种机制 人γ/delta-t细胞可以获得对凋亡的抗性，这是 途径是调节生存的重要决定因素（和 因此，γ/delta-T细胞的功能）。这个基本问题将是 主要在特定目标1中解决，我们建议检查分子 CD2介导的IL-12依赖性信号传导的细胞和细胞后果 γ/delta-t细胞相对于抑制细胞凋亡。第二个 问题与我们的总体假设有关： 抗凋亡的γ/delta-T细胞，很容易在培养中扩展 - 但 保留内在或先天MHC无限制的抗肿瘤细胞毒性 - 可以 提供一种重要手段来检查临床前生物学和 抗细胞凋亡的人γ/delta-T细胞的直接临床潜力作为一种 黑色素瘤的新型收养细胞免疫疗法。这个问题将是 在特定目标2和特定目标3中解决，我们将定义生物学 由抗凋亡的伽玛/delta-t介导的抗肿瘤细胞毒性 针对人黑色素瘤细胞的细胞。这些研究的关键特征是我们 将检查抗细胞凋亡的γ/delta-T的先天抗肿瘤活性 来自正常个体和黑色素瘤患者的细胞。 最终，我们将直接确定黑色素瘤反应是否反应 可以鉴定并在 来自外周血和原发性肿瘤样品的体外（γ/delta-t 从患有患者的患者获得的细胞肿瘤浸润淋巴细胞或TIL 黑色素瘤。这些发现可能为理性设计提供了基础 未来治疗黑色素瘤或其他治疗的免疫疗法试验 恶性肿瘤。