Antigen Discovery and Development of Tumor-Specific Lymphoma Immunotherapy

描述（由申请人提供）：本资助计划的目的是为候选人Sattva S. Neelapu, m.d.提供经验，投入时间和必要的培训，使其成为淋巴瘤研究中独立的以患者为导向的转化研究人员。Neelapu博士是一名内科科学家，接受过癌症免疫治疗的实验室培训和淋巴瘤医学肿瘤学的临床培训。该奖项将使他能够将75%的精力集中在职业发展和拟议的研究上。主动免疫疗法是治疗b细胞非霍奇金淋巴瘤的一种很有前途的方法。我们之前已经证明，由b细胞淋巴瘤免疫球蛋白分子重链和轻链的独特可变区域（称为独特型）制成的定制疫苗可以在超过80%的滤泡和套细胞淋巴瘤患者中诱导肿瘤特异性免疫。此外，疫苗接种与显著延长无病生存期相关，这表明主动免疫治疗可能会给淋巴瘤患者带来有意义的临床益处。然而，使用肿瘤特异性独特型作为疫苗的一个问题是，它需要为每个患者生产定制产品，这是昂贵的，费力的，耗时的。使用共同的淋巴瘤特异性肿瘤抗原将消除这些困难，但这些抗原迄今尚未被确定，因此尚未进行测试。我们建议在这里描述的研究中实现这两个目标。我们计划测试的中心假设是，接种肿瘤抗原的淋巴瘤患者会产生针对免疫原以及其他淋巴瘤相关抗原的广泛免疫反应，因此，来自这些患者的T细胞可以用作发现肿瘤抗原的工具。从独特型疫苗接种患者产生的肿瘤特异性t细胞系和克隆识别了从其他患者获得的几种hla匹配的淋巴瘤，这表明它们识别了共享的肿瘤抗原。本提案的具体目的是：1)利用cDNA表达克隆方法和来自先前接种过疫苗的患者的T细胞鉴定新的共享淋巴瘤特异性抗原。2)在Aim 1中鉴定的候选淋巴瘤抗原中确定t细胞表位。3)表征候选肿瘤抗原在各种淋巴瘤和正常组织中的表达模式。4)确定套细胞淋巴瘤患者多肽疫苗接种的安全性、免疫原性和临床活性。我们的长期目标是利用这些新发现的淋巴瘤患者肿瘤特异性抗原产生临床有效的疫苗。就其基本原理而言，这些由共享的免疫原性淋巴瘤特异性抗原制成的疫苗的重要临床益处是一种治疗方法，可以i)大大改善淋巴瘤患者的预后，ii)在这些患者中普遍使用。

DESCRIPTION (provided by applicant): The objective of this grant proposal is to provide the candidate, Sattva S. Neelapu, M.D., the experience, dedicated time, and training necessary to develop a career as an independent patient-oriented translational researcher in the study of lymphomas. Dr. Neelapu is a physician scientist with laboratory training in cancer immunotherapy and clinical training in lymphoma medical oncology. This award would allow him to focus 75% of his effort to career development and the proposed research. Active immunotherapy is a promising approach for the treatment of B-cell non-Hodgkin's lymphoma. We have previously demonstrated that customized vaccines made from the unique variable regions of the heavy and light chains of the B-cell lymphoma immunoglobulin molecule, termed idiotype, can induce tumor-specific immunity in greater than 80% of patients with follicular and mantle cell lymphoma. Furthermore, vaccination was associated with significantly prolonged disease-free survival, suggesting that active immunotherapy might induce meaningful clinical benefit in lymphoma patients. However, a problem with using tumor-specific idiotype as a vaccine is that it requires the generation of a custom-made product for each patient that is expensive, laborious, and time-consuming to make. The use of shared lymphoma-specific tumor antigens would obviate these difficulties, but such antigens have not been identified to date and thus have not been tested. We propose to achieve both in the research described here. The central hypothesis that we plan to test is that lymphoma patients vaccinated with a tumor antigen generate broad immune responses against the immunogen as well as other lymphoma-associated antigens and therefore, T cells from these patients can be used as tools for tumor antigen discovery. Tumor-specific T-cell lines and clones generated from idiotype-vaccinated patients recognized several HLA-matched lymphomas obtained from other patients, which suggested that they recognized a shared tumor antigen(s). The specific aims of this proposal are: 1) Identify novel shared lymphoma-specific antigen(s) using a cDNA expression cloning method and T cells from previously vaccinated patients. 2) Define T-cell epitopes in the candidate lymphoma antigen(s) identified in Aim 1. 3) Characterize the expression pattern of the candidate tumor antigen(s) in various lymphomas and normal tissues. 4) Determine the safety, immunogenicity, and clinical activity of peptide vaccinations in patients with mantle cell lymphoma. Our long-term goal is to generate clinically efficacious vaccines from these newly identified tumor-specific antigens in lymphoma patients. In terms of the rationale, the important clinical benefit of these vaccines made from shared immunogenic lymphoma-specific antigens is a treatment that can i) considerably improve the outcome in patients with lymphoma and ii) be used universally in these patients.