Project 2: Local immunotherapy corrects chemokine patterns in ovarian cancer

项目 2：局部免疫疗法纠正卵巢癌的趋化因子模式

• 批准号: 10362701
• 负责人: Robert Page Edwards
• 金额: $ 57.68万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-03 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10362701
• 关键词: Adjuvant Chemotherapy; Animal Experiments; Animals; Blood; CCL2 gene; CCL3 gene; CCR5 gene; CD8B1 gene; CXCL9 gene; CXCR3 gene; Cancer Model; Cancer Patient; Cells; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical effectiveness; Combined Modality Therapy; Data; Data Analyses; Dendritic Cells; Dinoprostone; Effectiveness; Effector Cell; Ensure; Evaluation; Half-Life; Human; Immune; Immunosuppression; Immunotherapy; Infiltration; Interferon Type II; Interferon alpha; Interleukin-10; Ligands; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mediator; Mus; NOS2A gene; Natural Killer Cells; Neoadjuvant Therapy; Operative Surgical Procedures; Outcome; PD-1 blockade; PD-1/PD-L1; PTGS2 gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Peritoneal Fluid; Phase; Phase I/II Trial; Production; Quality of life; RANTES; Randomized; Recurrence; Regimen; Regulatory T-Lymphocyte; Resectable; Resected; Resistance; Role; Safety; Signal Transduction; Site; System; TLR3 gene; TNF gene; Testing; Th1 Cells; Therapeutic; Therapeutic Effect; Transplantation; Treatment Protocols; Tumor Tissue; University of Pittsburgh Cancer Institute; Unresectable; Vaccinated; Vaccination; Vaccines; WFDC2 gene; arginase; cancer immunotherapy; celecoxib; chemokine; chemotherapy; cohort; design; efficacy clinical trial; follow-up; improved; insight; pre-clinical; preclinical study; primary endpoint; programmed cell death ligand 1; programmed cell death protein 1; programs; response; synergism; therapeutic effectiveness; tumor; tumor microenvironment

High numbers of CD8+ CTLs and low numbers of regulatory T(reg) cells in tumor microenvironments (TME) predicts prolonged survival of ovarian cancer (OvCa) patients and the clinical effectiveness of PD-1 blockers in other cancers. We observed strong synergy between TLR ligands, IFNα and COX2 blockers in specifically inducing the CTL-attracting chemokines, but suppressing Treg attractants in preclinical OvCa models. Combination of rintatolimod (TLR3-ligand), IFNα and celecoxib (chemokine-modulating regimen; CKM) promoted accumulation of tumor-specific CTLs in mouse OvCa TME, and synergized with PD-1 blockade in mice with PD-1 resistant ID8 tumors, resulting in long-term (>100 days) survival in 50% of the animals. We initiated a phase I/II trial (NCT02432378) to test if local (i.p.) rintatolimod/IFNα is safe and effective in guiding αDC1 vaccine-induced CXCR3+/CCR5+ CTLs to OvCa TME. We observed good tolerability of i.p. CKM and local elevation of CD8, PD-1, PD-L1 and PD-L2. We also observed that CKM-attracted CTLs and NK cells induce two separate (PD-1/PD-L1- and COX2-dependent), pathways of “secondary” immune suppression, providing rationale for their simultaneous targeting to achieve long-lasting therapeutic effects. We propose to: Aim 1: Determine the safety of i.p-administered CKM and its effectiveness in promoting local accumulation of CTLs in the TME of αDC1-vaccinated OvCa patients. Patients on phase II of NCT02432378 will receive neoadjuvant chemotherapy and αDC1 vaccination, with or without local (i.p.) CKM. We will evaluate the impact of i.p. CKM on the magnitude and duration of local CTL influx. We will obtain preliminary data on potential clinical impact of the CKM/αDC1-vaccine treatment on PFS and OS. Aim 2: Determine the mechanism of induction of “secondary” suppression in human OvCa TME in response to immune attack. We will test the hypothesis that CKM preferentially attracts CTLs, NK & Th1 cells (vs. MDSCs & Tregs), but that IFNγ/TNFα-production by these effector cells triggers two independent pathways of “secondary” suppression, mediated by PD-1/PD-L1/PD-L2 system and COX2/PGE2-system. Aim 3: Determine whether simultaneous targeting of PD-1 and COX2 results in sustained therapeutic effects of αDC1 vaccines. We will test if αDC1/CKM-activated CTLs activated PD-1/PD-L1 and COX2/PGE2- pathways in OvCa-bearing mice and if their complementary targeting results in therapeutic synergy. Guided by these results, we will finalize the design and will test if αDC1[tumor]/(CKM combined with PD-1 blockade will induce objective clinical responses (iRECIST) in patients with unresectable OvCa. Programmatic Role: The unique role of Project 2 is to evaluate the longitudinal effects of locally-administered CKM, interplay between vaccination, CKM and PD-1 blockade, and the roles of the PD-1/PD-L1/PD-L2 system vs. COX2/PGE2 systems, as complementary mediators of “secondary suppression” in TME.

肿瘤微环境（TME）中的CD8+ CTL数量高和数量少。 预测卵巢癌（OVCA）患者的长期生存期以及PD-1阻滞剂在 其他癌症。我们观察到TLR配体，IFNα和COX2阻滞剂之间的强烈协同作用。 诱导CTL吸引趋化因子，但在临床前OVCA模型中抑制了Treg景点。 Rintatolimod（TLR3-Ligand），IFNα和Celecoxib（趋化因子调节方案； CKM）的组合 促进了小鼠OVCA TME中肿瘤特异性CTL的积累，并与PD-1封锁协同 具有PD-1抗ID8肿瘤的小鼠，在50％的动物中导致长期（> 100天）的生存率。我们 启动了I/II期试验（NCT02432378），以测试局部（i.p.）Rintatolimod/IFNα是否安全有效地指导 αDC1疫苗诱导的CXCR3+/CCR5+ CTLS到OVCA TME。我们观察到了i.p.的良好耐受性CKM和 CD8，PD-1，PD-L1和PD-L2的局部升高。我们还观察到CKM吸引的CTL和NK细胞 诱导两个单独的（pd-1/pd-l1-和cox2依赖性），“次级”免疫抑制的途径， 为他们的同时定位提供理由，以实现持久的治疗作用。我们建议： AIM 1：确定I.P管理的CKM的安全性及其在促进本地的有效性 CTL在αDC1接种OVCA患者的TME中的积累。在第二阶段的患者 NCT02432378将接受新辅助化疗和αDC1疫苗接种，有或没有局部（i.p.）CKM。 我们将评估i.p.的影响CKM关于局部CTL影响的大小和持续时间。我们将获得 关于CKM/αDC1-疫苗治疗对PFS和OS的潜在临床影响的初步数据。 目标2：确定人类OVCA TME中“次级”抑制的机理 对免疫攻击的反应。我们将测试CKM优先吸引CTL，NK和TH1的假设 细胞（与MDSC和Tregs相比），但是这些效应细胞产生的IFNγ/TNFα产生会触发两个独立的 “次级”抑制的途径，由PD-1/PD-L1/PD-L2系统和COX2/PGE2-SYSTEM介导。 目标3：确定同时靶向PD-1和COX2是否会导致持续治疗 αDC1疫苗的作用。我们将测试αDC1/CKM激活的CTL激活PD-1/PD-L1和COX2/PGE2-- 含有OVCA的小鼠的途径及其完整的靶向导致热协同作用。指导 这些结果，我们将最终确定设计，并将测试是否αDC1[肿瘤]/（CKM与PD-1封锁合并将 在无法切除的OVCA患者中诱导客观临床反应（IRECIST）。 程序化作用：项目2的独特作用是评估本地管理的纵向影响 CKM，疫苗接种之间的相互作用，CKM和PD-1封锁以及PD-1/PD-L1/PD-L2系统的作用 与COX2/PGE2系统，作为TME中“次级抑制”的完整介体。