Project 1: Combinatorial adjuvants promote uniform and selective intratumoral CTL infiltration in colorectal cancer

项目1：组合佐剂促进结直肠癌瘤内CTL的均匀和选择性浸润

• 批准号: 10362700
• 负责人: Pawel Kalinski
• 金额: $ 50.21万
• 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/10362700
• 关键词: Adjuvant; Aftercare; Antigens; Autologous; Biometry; Biopsy; Cells; Clinical; Collaborations; Colorectal Cancer; Data; Data Analyses; Effectiveness; Evaluation; Funding; Heterogeneity; Image; Immune; Immunity; Immunization; Immunologics; Immunotherapy; In Vitro; Infiltration; Inpatients; Interferon Type II; Interferon alpha; Lesion; Ligands; Liver; MC38; Malignant Neoplasms; Microsatellite Instability; Microsatellite Repeats; Modeling; Multicenter Trials; Mus; Myeloid Cells; Natural Killer Cells; Neoplasms in Vascular Tissue; PD-1 blockade; PD-1/PD-L1; PTGS2 gene; Patients; Pattern; Peptides; Periodicity; Phase; Phase I/II Trial; Poly I-C; Production; Regimen; Resistance; Rest; Role; Safety; Specificity; Stromal Cells; System; T-Lymphocyte; TLR3 gene; TNF gene; Testing; Therapeutic; Therapeutic Effect; Tissues; Treatment Efficacy; Tumor Burden; Tumor Promotion; Tumor Tissue; Tumor-infiltrating immune cells; Vaccination; Vaccines; anti-PD-1; anti-cancer; anticancer activity; antitumor effect; celecoxib; chemokine; clinical efficacy; colon cancer patients; combinatorial; conditioning; data dissemination; design; effective therapy; effectiveness evaluation; human data; immune checkpoint blockade; immunogenic; improved; in vivo; in vivo Model; individual patient; metastatic colorectal; novel; patient response; patient subsets; pembrolizumab; phase 1 testing; phase I trial; phase II trial; pre-clinical; preclinical study; predict responsiveness; programmed cell death ligand 1; programmed cell death protein 1; programs; prospective; response; standard care; success; synergism; tissue culture; tool; tumor; tumor heterogeneity; tumor microenvironment

PROJECT 1: ABSTRACT CTL infiltration of tumor microenvironments (TME) predicts prolonged survival of patients with colorectal cancer (CRC). It also differentiates between the small subset of patients (<5%) with microsatellite instability- high [MSI-H] CRC, who show high levels of intratumoral CTLs and respond to PD-1 blockade from the rest of CRC patients who do not respond. Our preliminary data demonstrate that a) TLR3-based adjuvants induce CTL-attracting chemokines selectively in tumor stroma, but not surrounding non-tumor tissues; b) that combination of TLR3 ligands (such as rintatolimod) with IFNα synergistically induce high levels of CTL- attractants uniformly in all tumor lesions; and c) that inclusion of COX2 blockers enhances specificity of CKM in promoting CTL attraction but suppressing Treg attraction. The three-component chemokine-modulatory regimen (CKM rintatolimod, IFNα celecoxib) enhanced intratumoral CTL accumulation, prolonged survival and synergized with PD1- and PD-L1 blockers in inducing cures (> 150 day survival) in mice with i.p. MC38 tumors, resistant to PD-1 blockade alone. We completed phase I evaluation of systemic (i.v) CKM in patients with liver- metastatic CRC (NCT01545141), observing its very good tolerability and improved ratios of CTL-to-Treg markers in TME (compared to our patients receiving standard care only). We propose to: Aim 1. Evaluate the in-patient immunologic effectiveness of i.v.- administered CKM to promote local CTL accumulation in liver-metastatic CRC lesions in phase IIa trial NCT03403634. Comparing pre- versus post-treatment tumor biopsies of 12 patients with liver-metastatic CRC, we will test if systemic CKM will abrogate the TME heterogeneity and uniformly increase CTL numbers in TMEs, but not in surrounding tissues. Aim 2. Evaluate the immune and antitumor effects of sequential versus cyclic application of CKM and PD1 blockade and the advantage of additional immunization for long-lasting anti-tumor benefit. In preclinical studies, we will test the hypotheses that the CKM-attracted DCs, NK cells and T cells will a) promote local and systemic tumor-specific immunity and b) will amplify the CKM-initiated intratumoral production of CTL attractants in an IFNγ and TNFα-dependent mechanism, resulting in sustained conditioning of the TME for continued antitumor activity of PD1 blockade, even in the absence of additional vaccination. Aim 3. Perform a phase I/II trial to test the clinical activity of CKM combined with PD-1 blockade in patients with microsatellite-stable (MSS) CRC. In phase I/II trial, we will evaluate the clinical efficacy (iORR; iRESIST) of CKM/anti-PD-1treatment in 19 patients with MSS-CRC, traditionally resistant to immunotherapy. Programmatic Role: The unique role of Project 1 is to evaluate the effectiveness, uniformity and tumor- selectivity of systemically-applied CKM and develop CKM-based treatments with sustained anticancer effect. Its success will provide us with a tool to extend the therapeutic benefit of immunotherapy to a particularly large group of patients with MSS-CRC and other cancers currently non-responsive to checkpoint blockade.

项目1：摘要 CTL肿瘤微环境（TME）预测延长结直肠患者的存活率 癌症（CRC）。它也不同于少数患者（<5％）的微卫星不稳定 高[MSI-H] CRC，他显示高水平的肿瘤内CTL，并对其余部分响应PD-1封锁 不反应的CRC患者。我们的初步数据表明，a）基于TLR3的调节器影响 在肿瘤基质中有选择性地吸引趋化因子，但却不围绕非肿瘤组织。 b）那 TLR3配体（例如Rintatolimod）与IFNα协同诱导高水平的CTL-的组合 在所有肿瘤病变中均匀的吸引剂； c）包含COX2阻滞剂会增强CKM的特异性 促进CTL吸引力，但抑制Treg吸引力。三成分趋化因子调节 方案（CKM Rintatolimod，IFNα塞来昔布）增强了肿瘤内CTL的积累，延长的存活率和 与腹腔注射的小鼠中，在诱导的疗法（> 150天存活）中与PD1和PD-L1阻滞剂协同作用。 MC38肿瘤， 仅靠PD-1封锁能力。我们在肝脏患者中完成了对全身性（i.v）CKM的I期评估。 转移性CRC（NCT01545141），观察其良好的耐受性和提高的CTL与Treg比率 TME中的标记（与我们的患者仅接受标准护理相比）。我们建议： 目标1。评估静脉内i.v.-管理CKM的住院免疫学有效性以促进局部 IIA阶段试验NCT03403634中的CTL积累。比较前与 治疗后的12例肝脏中CRC患者的肿瘤活检，我们将测试系统性CKM是否会 废除TME异质性，并均匀地增加TME中的CTL数量，但不会在周围的组织中增加。 AIM 2。评估CKM和循环应用的免疫和抗肿瘤效应 PD1桶和额外免疫的优势可用于持久的抗肿瘤益处。在 临床前研究，我们将测试CKM吸引的DC，NK细胞和T细胞的假设a）促进 局部和全身性肿瘤特异性免疫力以及b）将扩大CKM引起的CTL的肿瘤内产生 IFNγ和TNFα依赖机制中的吸引剂，导致TME持续调理 即使在没有其他疫苗接种的情况下，PD1阻滞的持续抗肿瘤活性也是如此。 AIM 3。执行I/II期试验，以测试CKM与PD-1阻滞的临床活性 微卫星稳定（MSS）CRC的患者。在I/II期试验中，我们将评估临床效率（IORR； 19例MSS-CRC患者的CKM/抗PD-1治疗的IRESIST），传统上对免疫疗法有抵抗力。 程序化作用：项目1的独特作用是评估有效性，均匀性和肿瘤 对系统应用的CKM的选择性并开发具有持续抗癌作用的基于CKM的治疗方法。 它的成功将为我们提供一种将免疫疗法的治疗益处扩展到特别大的工具 当前有MSS-CRC和其他癌症患者目前对检查点封锁的患者组。