Proj. 2: Combining immune checkpoint blockade with T cell activation

项目摘要2 免疫检查点阻断(CPB)已经彻底改变了许多癌症的护理，但临床试验使用抗- PD-1ICB对肾小球基底膜无明显疗效。GBM是一种免疫抑制很严重的肿瘤。 免疫抑制细胞类型、途径和介质促进的微环境(TME)。因此，它不是 令人惊讶的是，单一的CPB没有达到治疗预期。项目2的目标是改善患者 通过确定合理的联合治疗方法，确定抗PD-1/CTLA-4治疗基底膜的结果。 我们假设联合治疗可以改善抗PD-1/CTLA-4治疗对T细胞的启动和激活 将显著提高基底膜的反应率，将这些免疫“冷”瘤转化为“热”瘤。 肿瘤。根据我们的初步数据显示，在T细胞的不同阶段，PD-1的选择性丢失 分化可以促进或拮抗效应器和记忆分化，我们进一步假设 联合方案中PD-1/CTLA-4阻断的时机可能对保护性抗肿瘤T细胞产生至关重要的影响 细胞反应。项目2将使用评估时间的三种互补方法来测试这些假设 PD-1阻断联合疫苗接种、溶瘤病毒疫苗治疗或靶向治疗在 目的：1-确定多肽疫苗联合抗PD-1/CTLA-4治疗的效果 关于建立抗肿瘤免疫反应和发展免疫记忆；2- 测试在GBM细胞疫苗中加入溶瘤病毒Boost是否会进一步增加对抗PD的敏感性 1/CTLA-4；和3-评估小分子CDK4/6靶向治疗提高疗效的能力 抗PD-1/CTLA-4在GBM模型中的作用与所有项目的交互以及对所有核心的利用 建议书中所描述的。我们的发现将提供最佳的方法来结合治疗和洞察 免疫抑制的GBM微环境。这些数据将直接为组合设计提供理论依据 GBM患者未来临床试验的治疗方法。

Summary Project 2 Immune Checkpoint blockade (CPB) has revolutionized the care for many cancers, but clinical trials using anti- PD-1 ICB have not had significant efficacy in GBM. GBM has a profoundly immunosuppressive tumor microenvironment (TME) promoted by immunosuppressive cell types, pathways and mediators. Thus, it is not surprising that single CPB did not meet therapeutic expectations. The goal of Project 2 is to improve patient outcomes following anti-PD-1/ CTLA-4 therapy in GBM by identifying rational combination therapy approaches. We hypothesize that combining therapies to improve T cell priming and activation with anti-PD-1/ CTLA-4 therapy will significantly increase response rates in GBM, converting these immunologically “cold” tumors into “hot” tumors. Based on our preliminary data showing that selective loss of PD-1 at different stages of T cell differentiation can either promote or antagonize effector and memory differentiation, we further hypothesize that the timing of PD-1/ CTLA-4 blockade in combinatorial regimens may critically influence protective anti-tumor T cell responses. Project 2 will test these hypotheses using three complementary approaches that evaluate timing of PD-1 blockade combined with vaccination, oncolytic virus vaccine therapy, or targeted therapies in the following aims: 1- Determine the effect of peptide vaccination combined with anti-PD-1/ CTLA-4 therapy on the establishment of anti-tumor immune responses and development of immunological memory; 2- Test if addition of an oncolytic virus boost to GBM cell vaccine further increases sensitivity to anti-PD- 1/ CTLA-4; and 3- Evaluate the ability of small molecule CDK4/6 targeted therapies to enhance therapeutic benefit of anti-PD-1/ CTLA-4 in GBM models. Interactions with all Projects and utilization of all Cores are described in the Proposal. Our findings will provide optimal ways to combine therapies and insights into the immunosuppressive GBM microenvironment. These data will directly inform the rationale design of combination therapies for future clinical trials for GBM patients.