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

描述（由申请人提供）：对癌症的天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。目前的方法包括免疫系统的非特异性刺激，肿瘤特异性抗原的主动免疫，以及过继细胞治疗-肿瘤特异性T细胞的转移。最近，我们研究了过继细胞疗法治疗淋巴瘤1。这种方法的疗效令人印象深刻，可以治愈大肿瘤。具体来说，我们使用主动免疫来产生抗肿瘤T细胞，并将这些T细胞转移到淋巴细胞耗尽的受体小鼠中。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。这种疫苗将肿瘤抗原与非特异性免疫刺激剂结合在一起：辐照过的肿瘤细胞（肿瘤抗原的丰富来源）载有TLR激动剂CpG（一种免疫刺激剂）。由该疫苗诱导的T细胞可以介导抗肿瘤免疫应答，并且当过继转移到淋巴细胞耗竭小鼠时更有效。本文提出的研究将利用我们独特的实验模型来解决过继细胞治疗面临的两个重要挑战。目的1阐述抗肿瘤T细胞的诱导方法和机制.我们正在开发这种治疗方法，用于治疗套细胞淋巴瘤的临床试验评估。更好地了解供体疫苗接种和体外免疫测定的持续验证将影响临床试验设计。目的2探讨CD 4记忆T细胞在抗肿瘤免疫中的作用。具体来说，我们将试图描述一个CD 4记忆干细胞。公认的是，CD 8记忆T细胞具有与长期造血干细胞相似的遗传特征37。最近的工作已经表征了这种CD 8 T细胞群体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，以确定是否存在CD 4记忆干细胞群，以及它是否对T细胞介导的抗肿瘤免疫应答很重要。 公共卫生相关性：癌症免疫疗法旨在增强对肿瘤的自然免疫反应，使其更有效。一种方法-过继细胞疗法-涉及肿瘤特异性T细胞的转移。这项研究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过继细胞疗法相关：（1）研究用于产生抗肿瘤T细胞的新疫苗，以及（2）了解介导有效抗肿瘤免疫应答的特定细胞群。这些研究具有直接的临床相关性，并将为癌症免疫治疗领域贡献重要知识。

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.