Antigen-specific T-cell activation, application to vacci

抗原特异性T细胞激活，在疫苗中的应用

• 批准号: 7331380
• 负责人: JAY A BERZOFSKY
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7331380
• 关键词: Antigen; specific; cell; activation; application

In the cancer immunology and immunotherapy arena, we have solved a major paradox in the role of NKT cells in tumor immunosurveillance, as NKT cells have been reported by others to protect, and by us to suppress tumor immunosurveillance. We found that type I NKT cells (carrying the invariant V?14J?18 T cell receptor) contribute to tumor immunity, whereas the type II NKT cells (with non-invariant receptor) are sufficient to suppress tumor immunosurveillance. We also showed that the type II NKT cell is the main cell suppressing immunosurveillance in 4 tumor models in which the classic CD4+CD25+ T regulatory cell does not play a role. We also found that blockade of the downstream mediator of this pathway, TGF-beta, can synergize with an anti-cancer vaccine in mice, increasing the T cell response and more completely inhibiting growth of an established tumor (cervical cancer model) than the vaccine alone. The protection is CD8 T cell-dependent. We have just opened a phase I clinical trial of a human anti-TGF-beta monoclonal antibody in melanoma and renal cell cancer patients in the NIH Clinical Center as part of a CRADA with Genzyme Corporation. If successful, the intent is to use this agent in conjunction with a cancer vaccine. We also found that a recombinant adenovirus expressing Her-2 can prevent appearance of spontaneous autochthonous breast cancers in BALB-neuT Her-2 transgenic mice. The mechanism is antibody mediated and requires CD4 T cells only for help, and does not require CD8 cells. However, the protection is not FcR dependent, unlike that of Herceptin, so the antibody induced by the vaccine appears to block signal transduction by the oncoprotein, rather than induce killing by ADCC. This cancer vaccine may be more effective for breast cancer than the monoclonal Herceptin, because the patient would make her own antibodies and these would not be dependent on FcR-mediated mechanisms. We are working with a collaborator to develop an adenovirus expressing human Her-2 in preparation for a clinical trial in human breast cancer, and have had pre-pre-IND discussions with the FDA. We have mapped a new epitope presented by HLA-B7 from the PAX-FKHR fusion protein unique to and expressed by 85% of alveolar rhabdomyosarcoma patients. In addition, we have mapped HLA-A2-restricted epitopes from 4 new cancer antigens studied in collaboration with Ira Pastan's lab, all expressed in prostate cancer but several also expressed in breast cancer and some other tumors. We have modified their sequences by epitope enhancement to make them more immunogenic, and have shown killing of human tumor cells by T cells specific for the first two of these. The first of these to be developed, TARP, is the subject of our planned clinical trial in prostate cancer patients that has been approved by the PRMC but has been delayed in obtaining an IND because of personnel turnover in the NIH Clinical Center Department of Transfusion Medicine that will prepare the dendritic cells for immunization, and because of changes at CTEP in decisions about IND filing. We hope that this trial will be opened within a few months.In the HIV and viral vaccine arena, first in studies also applicable to cancer vaccines, we have found that IL-15 expression by a vaccine will lead to induction of higher avidity cytotoxic T lymphocytes (CTL) that more effectively clear virus infections (or kill tumor cells). We also found that IL-15 will overcome the lack of CD4 T cell help in CD4 deficient animals, allowing induction of long-lived memory CTL that otherwise would not be induced without CD4 help. This may be a critical finding for therapeutic vaccines for HIV, for which it will be necessary to immunize HIV-infected or cancer patients with a deficiency of CD4 T cell help. We have also carried out epitope enhancement of HIV helper and CTL epitopes presented by human class II and class I HLA molecules, to make improved HIV vaccine constructs.

在癌症免疫学和免疫疗法领域，我们在NKT细胞在肿瘤免疫监视中的作用中解决了一个主要的悖论，因为其他人已经报道了其他人保护NKT细胞以保护NKT细胞，并抑制了抑制肿瘤免疫监视。我们发现，I型NKT细胞（携带不变的V？14J？18 T细胞受体）有助于肿瘤免疫，而II型NKT细胞（具有非变相受体）足以抑制肿瘤免疫监测性。我们还表明，II型NKT细胞是4种肿瘤模型中抑制免疫监视的主要细胞，其中经典的CD4+ CD25+ T调节细胞不起作用。我们还发现，该途径的下游介体TGF-β可以与小鼠中的抗癌疫苗协同作用，从而增加了T细胞反应并更加完全抑制已建立的肿瘤（宫颈癌模型）的生长。保护是CD8 T细胞依赖性的。我们刚刚在NIH临床中心的黑色素瘤和肾细胞癌患者中开设了人类抗-TGF-β单克隆抗体的I期临床试验，这是Genzyme Corporation的CRADA的一部分。如果成功的话，目的是将该药物与癌症疫苗结合使用。我们还发现，表达HER-2的重组腺病毒可以防止在BALB-SENUT HER-2转基因小鼠中出现自发的自发乳腺癌。该机理是介导的抗体，仅需要CD4 T细胞才能帮助，并且不需要CD8细胞。但是，与赫赛汀不同，保护并不取决于FCR，因此疫苗诱导的抗体似乎阻止了癌蛋白的信号转导，而不是诱导ADCC杀死。这种癌症疫苗对乳腺癌可能比单克隆赫赛汀更有效，因为患者会制作自己的抗体，并且这些抗体不会取决于FCR介导的机制。我们正在与合作者合作开发表达人类HER-2的腺病毒，以准备在人类乳腺癌中进行临床试验，并与FDA进行了预先讨论。我们已经绘制了由HLA-B7提出的新表位，由PAX-FKHR融合蛋白独有，由85％的肺泡横纹肌肉瘤患者表达并表达。此外，我们已经绘制了与IRA Pastan的实验室合作研究的4种新癌症抗原的HLA-A2限制表位，这些抗原均在前列腺癌中表达，但有几个在乳腺癌和其他肿瘤中也表达。我们通过表位增强来修改它们的序列，以使其更加免疫原性，并显示了针对其中前两个细胞对人类肿瘤细胞杀死的人类肿瘤细胞。 TARP中的第一个是我们计划的前列腺癌患者计划的临床试验的主题，该试验已获得PRMC批准，但由于NIH临床输血医学中的人员失误而被推迟获得IND，这将使树突状细胞为免疫化和IND申请Decives in Deceps的变化做好准备。我们希望该试验将在几个月内开放。在HIV和病毒疫苗领域，首先在研究中也适用于癌症疫苗，我们发现疫苗的IL-15表达将导致较高的患病性细胞毒性T淋巴细胞（CTL）诱导，从而更有效地清除病毒感染（或杀死肿瘤细胞）。我们还发现，IL-15将克服缺乏CD4缺乏动物的CD4 T细胞帮助，从而允许诱导长寿命的记忆CTL，否则在没有CD4帮助的情况下不会诱发。这可能是HIV治疗疫苗的关键发现，为此，有必要对患有CD4 T细胞帮助不足的HIV感染或癌症患者进行免疫。我们还对人类II和I类HLA分子提出的HIV助手和CTL表位进行了表位增强，以改善HIV疫苗构建体。