Project 1

项目1

• 批准号: 10473673
• 负责人: KUNLE O. ODUNSI
• 金额: $ 28.48万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473673
• 关键词: Address; Antigens; Bioinformatics; Biometry; Blood Vessels; CD44 gene; CD8B1 gene; CXCL12 gene; CXCR4 gene; Cancer Model; Cancer Patient; Cells; Chemoresistance; Clinical; Clinical Trials; Combination immunotherapy; Cyclic GMP; Cytolysis; Data; Dendritic Cells; Doxorubicin; Drug resistance; Engineering; Epithelial ovarian cancer; Exhibits; Extravasation; Frequencies; Functional disorder; Funding; Goals; Histopathology; Immune; Immune checkpoint inhibitor; Immune system; Immunologics; Immunosuppression; Immunotherapy; Ligands; Liposomal Doxorubicin; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mediator of activation protein; Memory; Molecular; Mus; Mutation; Myeloid-derived suppressor cells; Non-Small-Cell Lung Carcinoma; Oncolytic viruses; PD-1/PD-L1; PD-L1 blockade; Pathogenesis; Pathway interactions; Patients; Phase I/II Clinical Trial; Phase I/II Trial; Platinum; Population; Pre-Clinical Model; Production; Proto-Oncogene Protein c-kit; Refractory; Regimen; Regulatory T-Lymphocyte; Relapse; Reporting; Research Personnel; Resistance; Serous; T cell response; T cell therapy; T memory cell; T-Lymphocyte; Testing; Toxic effect; Tumor Antigens; Tumor Expansion; Tumor Immunity; Up-Regulation; Variant; Vascular Endothelial Growth Factors; Vascular Endothelium; Viral Vector; antagonist; anti-tumor immune response; antigen-specific T cells; base; cancer cell; cell motility; checkpoint receptors; chemotherapy; clinical efficacy; clinically translatable; combinatorial; endothelial stem cell; exhaustion; first-in-human; immune checkpoint; immune resistance; immunogenic; immunogenic cell death; immunogenicity; improved; in vivo; innovation; intraperitoneal; intravital microscopy; lymphocyte trafficking; melanoma; neoantigens; oncolytic vaccinia virus; ovarian neoplasm; programmed cell death ligand 1; programmed cell death protein 1; proteogenomics; recruit; resistance mechanism; standard of care; stemness; success; systemic toxicity; trafficking; translatable strategy; translational impact; tumor; tumor immunology; tumor microenvironment; tumor progression

PROJECT SUMMARY The goal of our studies is to generate robust and long-lasting tumor-specific T cell responses for durable tumor regression in patients with chemotherapy-resistant high-grade serous ovarian cancer (HGSOC). Although immunotherapy using immune checkpoint inhibitors (ICI), adoptive T cell therapy (ACT), or oncolytic viruses (OV) have generated remarkable results in several tumor types (e.g. melanoma, NSCLC), long-term tumor control has been infrequent in patients with HGSOC. Studies by our group and others have identified key stumbling blocks underpinning the limited anti-tumor efficacy of immunotherapy in EOC. These include: (i) insufficient expansion of tumor antigen-specific T cells, (ii) recruitment of Tregs and myeloid-derived suppressor cells (MDSC) via tumor CXCL12 production, (iii) severe dysfunction of tumor-infiltrating T lymphocytes (TIL) often by PD1 upregulation, (iv) low intrinsic tumor immunogenicity partially dependent on reduced tumor mutation burden and IFNβ production, (viii) insufficient recruitment of intratumoral dendritic cell populations (DC) capable of cross-presenting tumor antigens; (ix) tumor “vascular checkpoint” characterized by disorganized and tortuous tumor vasculature lacking adequate flow dynamics to support trafficking of anti- tumor T cells. While combinatorial immunotherapy strategies have the potential to overcome these immune resistance mechanisms in the tumor microenvironment (TME), they are often associated with unacceptably high rates of toxicities in patients. Our proposal addresses these stumbling blocks using innovative, clinically- translatable strategies to reprogram the TME and to identify mechanisms that drive or hinder T cell trafficking into ovarian tumors. We previously demonstrated blockade of the CXCL12/CXCR4 axis in the ovarian TME by intraperitoneal delivery of an oncolytic vaccinia virus expressing a CXCR4 antagonist (OVV-CXCR4-A-Fc) reduced intratumoral accumulation of immunosuppressive mediators, stimulated spontaneous anti-tumor immunity to endogenous tumor antigens, and improved T cell trafficking into the TME. Based on our observations, we propose to test the hypothesis that in HGSOC patients receiving liposomal doxorubicin (DOX) for platinum resistant/refractory EOC, in vivo tumor destruction by OVV-CXCR4-A-Fc will (i) abrogate tumor immune suppression, (ii) promote trafficking and accumulation of tumor-specific T cells, and (iii) when combined with PDL1 blockade, will limit T exhaustion and provide clinical benefit in a phase I/II clinical trial. The approach is to first determine whether i.p. OVV-CXCR4-A-Fc is safe and triggers a transformation of the ovarian TME from tolerogenic to immunogenic in a first-in-human clinical trial focused on patients with platinum resistant/refractory EOC. Second, we will determine whether the combination of OVV-CXCR4-A-Fc and PDL1 inhibition is safe and can generate clinical efficacy. Third, we will test whether the combinatorial regimen generates functionally distinct CD8+ and CD4+ effector/memory cells for shared antigens and neoantigens. Finally, we plan to uncover the molecular mechanisms by which OVV-CXCR4-A-Fc overcomes the ovarian tumor “vascular checkpoint” to enhance T cell migration and trafficking.

项目摘要 我们研究的目标是产生稳健和持久的肿瘤特异性T细胞应答，以实现持久的免疫治疗。 化疗耐药的高级别浆液性卵巢癌（HGSOC）患者的肿瘤消退。 尽管使用免疫检查点抑制剂（ICI）的免疫疗法、过继性T细胞疗法（ACT）或溶瘤疗法（ICSI）已被广泛应用。 病毒（OV）在几种肿瘤类型（如黑色素瘤、NSCLC）中产生了显著的效果， HGSOC患者的肿瘤控制不常见。我们小组和其他人的研究发现， 免疫疗法在EOC中抗肿瘤疗效有限的关键绊脚石。这些措施包括： 肿瘤抗原特异性T细胞的扩增不足，（ii）T细胞和骨髓源性T细胞的募集 抑制细胞（MDSC）通过肿瘤CXCL 12的生产，（iii）严重功能障碍的肿瘤浸润性T细胞， （iv）低的内在肿瘤免疫原性，部分依赖于 肿瘤突变负荷和IFNβ产生减少，（viii）肿瘤内树突状细胞募集不足 （ix）肿瘤“血管检查点”，其特征在于 紊乱和曲折的肿瘤血管系统缺乏足够的流动动力学来支持抗肿瘤药物的运输。 肿瘤T细胞虽然组合免疫治疗策略有可能克服这些免疫缺陷， 肿瘤微环境（TME）中的耐药机制，它们通常与不可接受的 患者的毒性反应率较高。我们的建议使用创新的，临床上的- 可翻译的策略，以重新编程TME，并确定驱动或阻碍T细胞运输的机制 卵巢肿瘤 我们先前证实了通过腹腔注射阻断卵巢TME中的CXCL 12/CXCR 4轴， 表达CXCR 4拮抗剂的溶瘤牛痘病毒（OVV-CXCR 4-A-Fc）的递送降低 免疫抑制介质的肿瘤内积累，刺激自发抗肿瘤免疫， 内源性肿瘤抗原，并改善T细胞向TME的运输。根据我们的观察，我们 我建议检验一个假设，即在接受脂质体阿霉素（DOX）治疗的HGSOC患者中， 对于耐药/难治性EOC，OVV-CXCR 4-A-Fc的体内肿瘤破坏将（i）消除肿瘤免疫应答， 抑制，（ii）促进肿瘤特异性T细胞的运输和积累，和（iii）当与 PDL 1阻断将限制T细胞耗竭，并在I/II期临床试验中提供临床益处。该方法是 为了首先确定腹膜内OVV-CXCR 4-A-Fc是否安全并触发卵巢TME从 在一项针对铂类药物患者的首次人体临床试验中， 耐药/难治性EOC。其次，我们将确定OVV-CXCR 4-A-Fc和PDL 1的组合是否 抑制是安全的且可产生临床功效。第三，我们将测试组合方案是否 产生功能上不同的CD 8+和CD 4+效应/记忆细胞，用于共享抗原和新抗原。 最后，我们计划揭示OVV-CXCR 4-A-Fc克服卵巢癌的分子机制。 肿瘤“血管检查点”，以增强T细胞的迁移和运输。