Adoptive cell therapy for lymphoma: A study on the role of CD4 memory T cells in

淋巴瘤的过继细胞疗法：CD4 记忆 T 细胞在淋巴瘤中的作用研究

• 批准号: 7912482
• 负责人: Matthew Jordan Goldstein
• 金额: $ 3.07万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-15 至 2012-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7912482
• 关键词: Active Immunization; Address; Agonist; Biological Assay; Biological Models; CD8B1 gene; Cell Therapy; Cells; Clinical Trials; Clinical Trials Design; Combined Vaccines; Experimental Models; Fellowship; Goals; Hematopoietic; Immune; Immune response; Immune system; In Vitro; Knowledge; Lymphoma; Malignant Neoplasms; Mantle Cell Lymphoma; Mediating; Memory; Methods; Mus; Population; Role; Source; Stem cells; T memory cell; T-Lymphocyte; Therapy Evaluation; Tumor Antigens; Tumor Immunity; Vaccination; Vaccines; Validation; Work; cancer immunotherapy; cell preparation; clinically relevant; genetic profiling; memory CD4 T lymphocyte; neoplastic cell; novel vaccines; prevent; public health relevance; stem; stem cell population; therapy development; tumor; tumor growth

DESCRIPTION (provided by applicant): Natural immune responses to cancer are usually insufficient to prevent tumor growth. Immunotherapy for cancer seeks to enhance these immune responses and make them more effective. Current approaches include non-specific stimulation of the immune system, active immunization with tumor-specific antigens, and adoptive cell therapy-the transfer of tumor-specific T cells. Recently, we have investigated adoptive cell therapy to treat lymphoma1. The efficacy of this maneuver is impressive and cures large tumors. Specifically, we use active immunization to generate anti-tumor T cells and transfer these T cells into lymphodepleted recipient mice. We refer to the preparation of these cells and subsequent transfer as immunotransplant. Currently, we are developing a new vaccine to induce anti-tumor T cells. This vaccine combines tumor antigens with a non-specific immune stimulant: irradiated-tumor cells (a rich source of tumor antigens) are loaded with the TLR agonist, CpG (an immune stimulant). The T cells induced by this vaccine can mediate anti-tumor immune responses and are more effective when adoptively transferred into lymphodepleted mice. The studies proposed here will take advantage of our unique experimental model to address two important challenges facing adoptive cell therapy. Aim 1 will elaborate on the methods and mechanisms of inducing anti- tumor T cells. We are developing this therapy for evaluation in a clinical trial to treat mantle cell lymphoma. A better understanding of donor vaccination and continued validation of in vitro immune assays will impact the clinical trial design. Aim 2 will investigate the role of CD4 memory T cells in anti-tumor immunity. Specifically, we will attempt to describe a CD4 memory stem cell. It is well accepted that CD8 memory T cells possesses similar genetic profiles to long-term hematopoietic stem cells37. Recent work has characterized the functional role of this CD8 T cell population in anti-tumor immunity4. Our model system provides a unique opportunity to determine if a CD4 memory stem cell population exists and whether it is important for T cell-mediated anti- tumor immune responses. PUBLIC HEALTH RELEVANCE: Immunotherapy for cancer seeks to enhance natural immune responses against tumors and make them more effective. One approach-adoptive cell therapy-involves the transfer of tumor-specific T cells. The work proposed in this fellowship has two goals related to an adoptive cell therapy we developed for treating lymphoma: (1) investigating a new vaccine for generating anti-tumor T cells and (2) understanding the specific cell populations that mediate effective anti-tumor immune responses. These studies have direct clinical relevance and will contribute important knowledge to the field of cancer immunotherapy.

描述（由申请人提供）：对癌症的自然免疫反应通常不足以防止肿瘤生长。癌症的免疫疗法旨在增强这些免疫反应并使其更有效。当前的方法包括对免疫系统的非特异性刺激，用肿瘤特异性抗原的主动免疫以及继发性细胞治疗 - 肿瘤特异性T细胞的转移。最近，我们研究了淋巴瘤1的收养细胞疗法。这种操作的功效令人印象深刻，可以治愈大肿瘤。具体而言，我们使用主动免疫来产生抗肿瘤T细胞，并将这些T细胞转移到淋巴结虫的受体小鼠中。我们将这些细胞的制备和随后的转移称为免疫移植。目前，我们正在开发一种新的疫苗来诱导抗肿瘤T细胞。该疫苗将肿瘤抗原与非特异性免疫刺激剂结合在一起：辐照肿瘤细胞（丰富的肿瘤抗原来源）用TLR激动剂CpG（免疫刺激剂）加载。该疫苗诱导的T细胞可以介导抗肿瘤的免疫反应，并且在采用转移到淋巴结中的小鼠中时更有效。此处提出的研究将利用我们独特的实验模型来应对采用细胞疗法面临的两个重要挑战。 AIM 1将详细说明诱导抗肿瘤T细胞的方法和机制。我们正在一项临床试验中开发用于评估的疗法，以治疗幔细胞淋巴瘤。更好地了解供体疫苗接种和对体外免疫测定的持续验证将影响临床试验设计。 AIM 2将研究CD4记忆T细胞在抗肿瘤免疫中的作用。具体来说，我们将尝试描述一个CD4存储干细胞。 CD8记忆T细胞具有与长期造血干细胞相似的遗传特征37。最近的工作是该CD8 T细胞群在抗肿瘤免疫中的功能作用。4。我们的模型系统提供了一个独特的机会来确定CD4记忆干细胞群是否存在，以及它对T细胞介导的抗肿瘤免疫反应是否重要。 公共卫生相关性：癌症的免疫疗法旨在增强对肿瘤的天然免疫反应并使其更有效。一种方法 - 辅助细胞治疗涉及肿瘤特异性T细胞的转移。该奖学金中提出的工作有两个目标与我们开发的用于治疗淋巴瘤的收养细胞疗法有关：（1）研究一种用于生成抗肿瘤T细胞的新疫苗，以及（2）了解介导有效抗肿瘤的特定细胞群体免疫反应。这些研究具有直接的临床相关性，并将为癌症免疫疗法领域提供重要知识。