Proteasome inhibitor (PS-341) and adoptive immunotherapy

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。这种增敏是通过c-FLIP的下调发生的，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，这种致敏活性也被证明与NF-kappaB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免疫疗法的杀伤潜力和骨髓移植（BMT）前的广泛细胞减少条件作用结合使用。为此，提出了几个特异性目标：特异性目标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TRAIL受体激动剂抗体（抗dr5）对晚期肿瘤小鼠的影响。

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.