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 肿瘤微环境 (TME) 的 CTL 浸润可预测结直肠癌患者的生存期延长 它还区分了一小部分具有微卫星不稳定性的患者（<5%）。 高 [MSI-H] CRC，显示出高水平的瘤内 CTL，并对其他肿瘤的 PD-1 阻断有反应 我们的初步数据表明，a) 基于 TLR3 的佐剂会诱导。 肿瘤基质中选择性吸引 CTL 趋化因子，但非肿瘤组织周围不存在 b) TLR3配体（如rintatolimod）与IFNα的组合协同诱导高水平的CTL- 引诱剂在所有肿瘤病变中均一；c) COX2 阻滞剂的加入增强了 CKM 的特异性 促进 CTL 吸引力但抑制 Treg 吸引力 三组分趋化因子调节。 方案（CKM rintatolimod、IFNα celecoxib）增强瘤内 CTL 积累，延长生存期并 与 PD1- 和 PD-L1 阻滞剂协同作用，诱导腹腔注射肿瘤小鼠的治愈（> 150 天存活）， 我们完成了对肝病患者全身（静脉注射）CKM 的 I 期评估。 转移性 CRC (NCT01545141)，观察到其非常好的耐受性和 CTL 与 Treg 比率的改善 TME 中的标志物（与仅接受标准护理的患者相比）我们建议： 目标 1. 评估静脉注射 CKM 的住院免疫效果，以促进局部治疗 IIa 期试验 NCT03403634 中肝转移性 CRC 病灶中 CTL 的积累情况与治疗前的比较。 对 12 名肝转移性 CRC 患者进行治疗后肿瘤活检，我们将测试全身 CKM 是否有效 消除 TME 异质性并一致增加 TME 中的 CTL 数量，但不增加周围组织中的 CTL 数量。 目标 2. 评估序贯与循环应用 CKM 和 CKM 的免疫和抗肿瘤作用 PD1 阻断和额外免疫的优势可实现持久的抗肿瘤益处。 在临床前研究中，我们将测试以下假设：CKM 吸引的 DC、NK 细胞和 T 细胞将 a) 促进 局部和全身肿瘤特异性免疫，b) 将放大 CKM 引发的 CTL 瘤内产生 IFNγ和TNFα依赖性机制中的引诱剂，导致TME的持续调节 即使在没有额外疫苗接种的情况下，PD1 阻断也能持续发挥抗肿瘤活性。 目标 3. 进行 I/II 期试验，测试 CKM 联合 PD-1 阻断剂在治疗中的临床活性 微卫星稳定（MSS）CRC患者在I/II期试验中，我们将评估临床疗效（iORR； iRESIST）对 19 名传统上对免疫疗法耐药的 MSS-CRC 患者进行 CKM/抗 PD-1 治疗。 计划作用：项目 1 的独特作用是评估有效性、均匀性和肿瘤- 系统应用 CKM 的选择性，并开发基于 CKM 的具有持续抗癌作用的治疗方法。 它的成功将为我们提供一个工具，将免疫疗法的治疗益处扩展到特别大的人群 一组患有 MSS-CRC 和其他癌症的患者目前对检查点封锁无反应。