Proteasome inhibitor (PS-341) and adoptive immunotherapy

蛋白酶体抑制剂（PS-341）和过继免疫疗法

• 批准号: 7026999
• 负责人: WILLIAM JOSEPH MURPHY
• 金额: $ 28.12万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7026999
• 关键词: CD95 molecule; antineoplastics; antitumor antibody; apoptosis; bone marrow transplantation; combination cancer therapy; cytotoxic T lymphocyte; genetically modified animals; graft versus host disease; immunocytochemistry; laboratory mouse; natural killer cells; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; passive immunization; protease inhibitor; proteasome; tumor infiltrating lymphocyte; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Proteasome inhibitors have shown promise in cancer therapy as a single agent. We have recently observed that the proteasome inhibitor, PS-341, can sensitize neoplastic cells to TRAIL-mediated death. This sensitization occurred through the down-regulation of c-FLIP, an important mediator in the prevention of apoptosis. Surprisingly, this sensitizing activity was also shown to be independent of NF-kappaB in some tumor lines. We now wish to extend these findings to ascertain if proteasome inhibition can be used in conjunction with the killing potential of adoptive immunotherapy and the extensive cytoreductive conditioning that precedes bone marrow transplantation (BMT). To do this, several Specific Aims are proposed: Specific Aim 1 will extend on the in vitro studies and examine the effects of PS-341 and a genetic construct for TRAIL (Fc-TRAIL) or a recently obtained agonist TRAIL receptor antibody (anti-DR5) on advanced tumor-bearing mice. The mechanism underlying the anti-tumor effects will also be dissected using TRAIL KO mice. Specific Aim 2 will assess the effects of PS-341, with or without Fc-TRAIL or anti-DR5, in a minimal residual disease model in which the tumor-bearing mice receive a bone marrow transplant (BMT). Both syngeneic and allogeneic BMT will be used and effects on immune and myeloid reconstitution as well as tumor relapse will be assessed. In allogeneic BMT models, effects on graft-versus-host disease (GVHD) will be ascertained. Finally, in Specific Aim 3, effects of PS-341 as a means to sensitize tumor cells to T and NK cell killing will be determined using both in vitro and in vivo assays. This will culminate with combining the data attained from the previous specific aims and assessing the effects of PS-341 with NK cells and anti-DR5 as an adoptive immunotherapy regimen in resting tumor-bearing mice and in tumor-bearing mice after BMT. These results will allow for the assessment of the efficacy of proteasome inhibition with PS-341 in conjunction with immunotherapy using a variety of tumor types and in preclinically-relevant models.

描述（由申请人提供）：蛋白酶体抑制剂作为单一药物在癌症治疗中显示出前景。我们最近观察到蛋白酶体抑制剂 PS-341 可以使肿瘤细胞对 TRAIL 介导的死亡敏感。这种致敏作用是通过 c-FLIP 的下调而发生的，c-FLIP 是预防细胞凋亡的重要介质。令人惊讶的是，在某些肿瘤系中，这种敏化活性也被证明与 NF-κB 无关。我们现在希望扩展这些发现，以确定蛋白酶体抑制是否可以与过继性免疫疗法的杀伤潜力以及骨髓移植（BMT）之前的广泛细胞减灭预处理结合使用。为此，提出了几个具体目标： 具体目标 1 将扩展体外研究，并检查 PS-341 和 TRAIL 基因构建体 (Fc-TRAIL) 或最近获得的激动剂 TRAIL 受体抗体（抗 DR5）对晚期荷瘤小鼠的影响。 抗肿瘤作用的机制也将使用 TRAIL KO 小鼠进行剖析。具体目标 2 将评估 PS-341（联合或不联合 Fc-TRAIL 或抗 DR5）在微小残留病模型中的效果，在该模型中，荷瘤小鼠接受骨髓移植 (BMT)。将使用同基因和同种异体 BMT，并评估对免疫和骨髓重建以及肿瘤复发的影响。在同种异体 BMT 模型中，将确定对移植物抗宿主病 (GVHD) 的影响。最后，在具体目标 3 中，将使用体外和体内测定来确定 PS-341 作为使肿瘤细胞对 T 和 NK 细胞杀伤敏感的手段的效果。最终将结合之前具体目标获得的数据，评估 PS-341 与 NK 细胞和抗 DR5 作为过继免疫治疗方案对静息荷瘤小鼠和 BMT 后荷瘤小鼠的影响。这些结果将有助于评估 PS-341 蛋白酶体抑制与多种肿瘤类型和临床前相关模型的免疫疗法相结合的疗效。