Antigen Discovery and Development of Tumor-Specific Lymphoma Immunotherapy

肿瘤特异性淋巴瘤免疫疗法的抗原发现和发展

• 批准号: 7623457
• 负责人: Sattva S Neelapu
• 金额: $ 13.61万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623457
• 关键词: Accounting; Active Immunotherapy; Antigens; Applications Grants; Autologous; Autologous Tumor Cell; Award; B-Cell Lymphomas; B-Cell NonHodgkins Lymphoma; B-Lymphocytes; Behavior Therapy; CD8B1 gene; Cell Line; Cells; Clinical; Complementary DNA; Custom; Development; Disease remission; Disease-Free Survival; Doctor of Medicine; Elements; Fatal Outcome; Follicular Lymphoma; Generations; Goals; Growth; Immune response; Immunity; Immunoglobulin Idiotypes; Immunoglobulin Variable Region; Immunoglobulins; Immunotherapy; Indolent; Laboratories; Light; Long-Term Survivors; Lymphoma; Malignant Neoplasms; Mantle Cell Lymphoma; Medical Oncology; Methods; Molecular; Neoplasms; Non-Hodgkin' s Lymphoma; Normal tissue morphology; Outcome; Patients; Pattern; Peptides; Physicians; Proteins; Relapse; Research; Research Personnel; Safety; Scientist; T-Lymphocyte; T-Lymphocyte Epitopes; Techniques; Testing; Time; Training; Tumor Antigens; Vaccinated; Vaccination; Vaccines; cDNA Expression; cDNA Library; cancer immunotherapy; career; career development; experience; expression cloning; immunogenic; immunogenicity; improved; melanoma; novel; outcome forecast; patient oriented; research study; response; tool; treatment response; tumor

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.

描述（由申请人提供）：该赠款建议的目的是为候选人提供Sattva S. Neelapu，M.D。，《经验，专门的时间和培训》，以发展为淋巴瘤研究中的独立面​​向患者的转化研究人员的职业。 Neelapu博士是一位医师科学家，接受了癌症免疫疗法和淋巴瘤医学肿瘤学临床培训的实验室培训。该奖项将使他能够将自己的75％的努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有前途的方法。我们先前已经证明，由B-细胞淋巴瘤免疫球蛋白分子的重链和轻度链的独特变量区域制成的定制疫苗可诱导大于80％的卵泡和地幔细胞淋巴瘤患者中80％的肿瘤特异性免疫。此外，疫苗接种与无病生存期显着延长有关，这表明主动免疫疗法可能会引起有意义的临床益处。但是，使用肿瘤特异性偶像作为疫苗的问题是，它需要为每位昂贵，费力且耗时的患者生成定制产品。共同淋巴瘤特异性肿瘤抗原的使用将消除这些困难，但迄今为止尚未确定此类抗原，因此尚未进行测试。我们建议在此处描述的研究中实现这两者。我们计划测试的中心假设是，用肿瘤抗原接种疫苗的淋巴瘤患者对免疫原以及其他与淋巴瘤相关的抗原产生广泛的免疫反应，因此，这些患者的T细胞可用作肿瘤抗原发现的工具。由白痴接种疫苗的患者产生的肿瘤特异性T细胞系和克隆识别从其他患者获得的几种HLA匹配的淋巴瘤，这表明他们认识到共用的肿瘤抗原。该提案的具体目的是：1）使用cDNA表达克隆方法和先前接种的患者的T细胞确定新型的共享淋巴瘤特异性抗原。 2）在AIM1。3中鉴定的候选淋巴瘤抗原（S）中定义T细胞表位。3）表征各种淋巴瘤和正常组织中候选肿瘤抗原的表达模式。 4）确定地幔细胞淋巴瘤患者肽疫苗接种的安全性，免疫原性和临床活性。我们的长期目标是从这些新发现的淋巴瘤患者中这些新发现的肿瘤特异性抗原中产生临床有效的疫苗。就基本原理而言，这些由共同的免疫淋巴瘤特异性抗原制成的这些疫苗的重要临床益处是一种治疗方法，可以大大改善淋巴瘤患者和II患者的预后）在这些患者中普遍使用。