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

项目。

• 批准号: 10210220
• 负责人: E. Antonio Chiocca
• 金额: $ 48.51万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-03 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10210220
• 关键词: Adult; Affect; Biological Assay; CD8-Positive T-Lymphocytes; CDK4 gene; CTLA4 blockade; CTLA4 gene; Caring; Cell Cycle; Cells; Clinical Trials; Combined Modality Therapy; Data; Development; Future; Genetic Transcription; Glioblastoma; Goals; Harvest; Immune; Immunocompetent; Immunologic Memory; Immunologics; Immunosuppression; KLRB1 gene; Maintenance; Malignant neoplasm of brain; Mediator of activation protein; Memory; Modeling; Mus; Oncolytic; Oncolytic viruses; Outcome; PD-1 blockade; Pathway interactions; Patient-Focused Outcomes; Patients; Peptide Vaccines; Phase I Clinical Trials; Prognosis; Regimen; Selection for Treatments; T cell differentiation; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Time; Treatment Efficacy; Tumor stage; Tumor-infiltrating immune cells; Vaccination; Vaccine Therapy; Vaccines; anti-CTLA-4 therapy; anti-PD-1; anti-PD1 therapy; anti-tumor immune response; base; cancer clinical trial; cell population study; cell type; checkpoint inhibition; combinatorial; design; efficacy testing; expectation; immune checkpoint blockade; immunogenic cell death; improved; insight; mouse model; novel therapeutics; peptide vaccination; pre-clinical; programmed cell death ligand 1; programmed cell death protein 1; response; small molecule; targeted treatment; tumor; tumor microenvironment; tumor-immune system interactions

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.

项目2概要 免疫检查点阻断（CPB）已经彻底改变了许多癌症的护理，但使用抗- PD-1 ICB在GBM中没有显著疗效。GBM有一个严重的免疫抑制肿瘤 免疫抑制细胞类型、途径和介质促进的TME。因而是不可 令人惊讶的是，单次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，在GBM中进行抗PD-1/ CTLA-4治疗后的结局。 我们假设，联合抗PD-1/ CTLA-4治疗以改善T细胞引发和活化， 将显著增加GBM的反应率，将这些免疫学上的“冷”肿瘤转化为“热”肿瘤， 肿瘤的基于我们的初步数据，显示PD-1在T细胞不同阶段的选择性丢失， 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阻断的时机可能严重影响保护性抗肿瘤T细胞 细胞反应。项目2将使用三种评估时间的互补方法来测试这些假设 PD-1阻断剂联合疫苗接种、溶瘤病毒疫苗治疗或靶向治疗， 1-确定肽疫苗接种与抗PD-1/ CTLA-4治疗组合的效果 抗肿瘤免疫应答的建立和免疫记忆的发展; 2- 测试向GBM细胞疫苗中添加溶瘤病毒加强是否进一步增加对抗PD的敏感性- 1/ CTLA-4;和3-评价小分子CDK 4/6靶向疗法增强治疗性免疫应答的能力。 抗PD-1/ CTLA-4在GBM模型中的益处。与所有项目的互动和所有核心的利用是 提案中所述。我们的发现将为联合收割机治疗和对肿瘤的深入了解提供最佳方法。 免疫抑制GBM微环境。这些数据将直接为组合的合理设计提供信息 用于未来GBM患者的临床试验。