Antigen Discovery and Development of Tumor-Specific Lymphoma Immunotherapy

描述(由申请人提供)：这项资助计划的目的是为候选人Sattva S.Neelapu，M.D.提供必要的经验、专门的时间和培训，以发展其在淋巴瘤研究中作为一名独立的面向患者的翻译研究人员的职业生涯。Neelapu博士是一名内科科学家，在癌症免疫治疗方面接受过实验室培训，在淋巴瘤内科肿瘤学方面接受过临床培训。这一奖项将使他能够将75%的精力集中在职业发展和拟议的研究上。主动免疫治疗是治疗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制成的定制疫苗，称为独特型，可以在80%以上的滤泡性和套细胞淋巴瘤患者中诱导肿瘤特异性免疫。此外，接种疫苗与显著延长无病生存期有关，这表明主动免疫治疗可能对淋巴瘤患者产生有意义的临床益处。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一种定制的产品，这是昂贵、费力和耗时的。使用共享的淋巴瘤特异性肿瘤抗原将消除这些困难，但此类抗原迄今尚未被鉴定，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。我们计划检验的中心假设是，接种肿瘤抗原的淋巴瘤患者会产生针对该免疫原和其他淋巴瘤相关抗原的广泛免疫反应，因此，这些患者的T细胞可以用作发现肿瘤抗原的工具。来自独特型疫苗接种患者的肿瘤特异性T细胞株和克隆识别来自其他患者的几个HLA型相合的淋巴瘤，这表明它们识别一个共同的肿瘤抗原(S)。该建议的具体目的是：1)利用基因表达克隆方法和既往接种过的患者的T细胞鉴定新的共同淋巴瘤特异性抗原(S)。2)确定候选淋巴瘤抗原(S)中的T细胞表位。3.确定候选肿瘤抗原(S)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的安全性、免疫原性和临床活性。我们的长期目标是从这些新发现的淋巴瘤患者的肿瘤特异性抗原中产生临床有效的疫苗。从原理上讲，这些由共同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，它可以：1)显著改善淋巴瘤患者的预后；2)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.