Gamma Delta T Cells--Immunotherapy for Melanoma

Gamma Delta T 细胞——黑色素瘤的免疫疗法

• 批准号: 6625723
• 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 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6625723
• 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/δ-T 细胞的增殖，但 通常可以诱导 γ/δ-T 细胞凋亡，从而阻止其发生 扩张。我们已经鉴定出 CD2 介导的、白细胞介素 (IL)-12 依赖性的 抑制丝裂原刺激的人细胞凋亡的信号通路 γ/δ-T 细胞。从生物学角度来看，这些发现具有重要意义，因为它们可能 有助于更好地理解这种或类似的信号传导途径 用于维持或调节体内γ/δ-T细胞区室。 此外，这些发现具有重要的现实意义： 利用这一信号通路，我们的实验室已经能够开发出 允许大规模体外扩增活细胞的方法， 抗凋亡人类 γ/δ-T 细胞，迄今为止的一项事业，还没有 可能的。同样重要的是，这些抗凋亡的 γ/δ-T 细胞（现在 容易获得）可以被证明可以调解显着的先天的，主要的 组织相容性复合物 (MHC) - 针对多种细胞的无限制细胞毒性 体外人类肿瘤细胞系，包括发现的黑色素瘤细胞系 对抗凋亡介导的细胞溶解极其敏感 γ/δ-T 细胞，但不包括对照 α/β-T 细胞。在这笔补助金中，有两 关于抗凋亡γ/δ-T 的不同但相关的问题 细胞将被解决：1）潜在的生物学机制是什么？ 增强抗凋亡 γ/δ-T 细胞的扩增和存活？ 以及，2）我们如何开始利用内在的优势来获得直接的临床益处？ 或由抗凋亡的γ/δ-T表现出的先天抗肿瘤特性 细胞？第一个问题可以重述为我们可检验的总体假设 即：CD2 介导的、IL-12 依赖性信号传导是一种机制，通过该机制 人类 γ/δ-T 细胞可以获得对细胞凋亡的抵抗力，并且这 途径是生存调节的重要决定因素（并且 因此，γ/δ-T 细胞的功能）。这个基本问题将是 主要在具体目标 1 中解决，我们建议检查分子 人类 CD2 介导的 IL-12 依赖性信号传导的细胞后果 γ/δ-T 细胞对细胞凋亡的抑制。第二个 问题与我们总体假设的推论有关，即： 抗凋亡的 γ/δ-T 细胞很容易在培养物中扩增 - 然而 保留内在或先天 MHC 不受限制的抗肿瘤细胞毒性 - 可以 提供了检查临床前生物学和临床前生物学的重要手段 抗凋亡人 γ/δ-T 细胞作为治疗药物的直接临床潜力 黑色素瘤的新形式过继细胞免疫疗法。这个问题将是 在具体目标 2 和具体目标 3 中讨论，我们将在其中定义生物学 抗凋亡γ/δ-T介导的抗肿瘤细胞毒性 细胞对抗人类黑色素瘤细胞。这些研究的一个关键特征是我们 将检查抗凋亡的 γ/δ-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是否具有反应性 抗凋亡的 γ/δ-T 细胞可以在以下环境中被识别和增殖： 从外周血和原发性肿瘤样本（γ/δ-T 细胞肿瘤浸润淋巴细胞（TIL）从患者体内获得 黑色素瘤。这些发现可为合理设计提供依据 未来治疗黑色素瘤或其他疾病的免疫疗法试验 恶性肿瘤。