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

描述(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，使其更加有效。目前的方法包括对免疫系统的非特异性刺激，肿瘤特异性抗原的主动免疫，以及过继细胞疗法-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。这种手法的疗效令人印象深刻，可以治愈大型肿瘤。具体地说，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一种非特异性免疫刺激剂结合在一起：照射后的肿瘤细胞(肿瘤抗原的丰富来源)含有TLR激动剂CpG(一种免疫刺激剂)。该疫苗诱导的T细胞可以介导抗肿瘤免疫反应，过继转移到淋巴枯竭的小鼠体内效果更好。这里提出的研究将利用我们独特的实验模型来解决采用细胞疗法面临的两个重要挑战。目的1阐述诱导抗肿瘤T细胞的方法和机制。我们正在开发这种疗法，以在治疗套细胞淋巴瘤的临床试验中进行评估。更好地了解捐赠者疫苗接种和体外免疫分析的持续验证将影响临床试验设计。目的2探讨CD4记忆T细胞在抗肿瘤免疫中的作用。具体地说，我们将尝试描述一种CD4记忆干细胞。众所周知，CD8记忆T细胞具有与长期造血干细胞相似的基因特征37。最近的工作表征了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是否存在CD4记忆干细胞群体，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。与我们开发的用于治疗淋巴瘤的过继细胞疗法相关的工作有两个目标：(1)研究一种产生抗肿瘤T细胞的新疫苗；(2)了解介导有效抗肿瘤免疫反应的特定细胞群。这些研究具有直接的临床意义，并将为癌症免疫治疗领域贡献重要的知识。

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.