Project 1

项目总结 我们研究的目标是产生强大而持久的肿瘤特异性T细胞反应 化疗耐药高级别浆液性卵巢癌(HGSOC)患者的肿瘤消退。 虽然使用免疫检查点抑制剂(ICI)、过继T细胞疗法(ACT)或溶瘤的免疫疗法 病毒(OV)在几种肿瘤类型(如黑色素瘤、非小细胞肺癌)中产生了显著的效果，长期 在HGSOC患者中，肿瘤控制并不常见。我们小组和其他人的研究发现 EOC免疫治疗抗肿瘤疗效有限的关键绊脚石。这包括：(I) 肿瘤抗原特异性T细胞扩增不足，(Ii)树突状细胞和髓系细胞的募集 通过肿瘤CXCL12的产生抑制细胞(MDSC)，(Iii)肿瘤浸润性T细胞严重功能障碍 淋巴细胞(TIL)通常由PD1上调，(Iv)低固有的肿瘤免疫原性部分依赖 减少肿瘤突变负担和干扰素β的产生，(Viii)瘤内树突状细胞募集不足 能够交叉呈递肿瘤抗原的人群(DC)；(Ix)肿瘤“血管检查点”，其特征为 紊乱和曲折的肿瘤血管缺乏足够的血流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 在肿瘤微环境(TME)中的耐药机制，它们经常与不可接受的 患者的高毒副作用。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细胞贩运的机制 变成卵巢肿瘤。 我们先前证实了通过腹膜腔内阻断卵巢TME中的CXCL12/CXCR4轴 表达CXCR4拮抗剂(OVV-CXCR4-A-Fc)的溶瘤痘苗病毒的递送减少 免疫抑制介质在肿瘤内的聚集，刺激自发的抗肿瘤免疫 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 建议对HGSOC患者接受脂质体阿霉素(DOX)治疗铂类药物的假设进行检验 OVV-CXCR4-A-Fc对耐/难治性EOC、体内肿瘤的杀伤作用将(I)消除肿瘤免疫 抑制，(Ii)促进肿瘤特异性T细胞的运输和积累，以及(Iii)与 PDL1阻断，将限制T细胞的消耗，并在I/II期临床试验中提供临床益处。方法是 首先要确定IP是否。OVV-CXCR4-A-Fc是安全的，并触发卵巢TME从 首次以铂类患者为研究对象的人类临床试验中对免疫原性的耐受性 耐/耐火EoC。其次，我们将确定OVV-CXCR4-A-FC和PDL1的组合 抑制是安全的，可以产生临床疗效。第三，我们将测试联合方案是否 为共享抗原和新抗原产生不同功能的CD8+和CD4+效应/记忆细胞。 最后，我们计划揭示OVV-CXCR4-A-Fc克服卵巢癌的分子机制 肿瘤的“血管检查点”加强T细胞的迁移和运输。

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.