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Targeting the Chemokine System to Sensitize Tumors to Immunotherapy

靶向趋化因子系统使肿瘤对免疫疗法敏感

基本信息

批准号：
10362635
负责人：
Pawel Kalinski
金额：
$ 287.59万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
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/10362635
关键词：
Adjuvant Affect Antigens Autologous Biological Markers Blood CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Cell Count Cell physiology Cells Clinical Clinical Data Clinical effectiveness Cohort Studies Colorectal Cancer Combined Modality Therapy Complement Correlative Study Cross-Priming Cytotoxic T-Lymphocytes Data Dendritic Cell Vaccine Development Dinoprostone Disease Effectiveness Effector Cell Future Goals Immune Immune system Immunologic Tests Immunologics Immunosuppression Immunotherapy Inpatients Interferon alpha Interferons Killer Cells Lesion Ligands Link Liver Malignant Neoplasms Malignant neoplasm of ovary Microsatellite Repeats Mus Myeloid-derived suppressor cells Natural Killer Cells Neoplasms in Vascular Tissue PD-1 blockade PD-1/PD-L1 Patients Pattern Peptide Vaccines Peptides Phase Prediction of Response to Therapy Productivity Program Research Project Grants Prostaglandins Refractory Regimen Regulatory T-Lymphocyte Resistance Safety Sequential Treatment Solid Neoplasm Specificity Standardization System T cell infiltration T cell therapy TLR3 gene TNF gene Testing Th1 Cells Therapeutic Therapeutic Effect Tissues Treatment Efficacy Vaccination Vaccinee Vaccines anti-PD-1 antitumor effect cancer type celecoxib checkpoint inhibition chemokine chemokine receptor clinical efficacy colon cancer patients combinatorial design immune checkpoint blockade immune checkpoint blockers immune clearance improved in situ vaccine in vivo Model melanoma metastatic colorectal neoplastic cell novel novel strategies novel therapeutics objective response rate phase I trial phase II trial pre-clinical preclinical study programmed cell death protein 1 programs prospective recruit refractory cancer response survival prediction tertiary lymphoid organ therapeutic effectiveness therapeutic vaccine therapy resistant tool translational study treatment optimization tumor tumor microenvironment

项目摘要

The revised P01CA234212 tests novel strategies to promote selective CTL entry into tumor micro- environments (TME) and sensitize “cold” tumors to immunotherapy. Our preclinical and early clinical data demonstrate that the chemokine-modulating (CKM) regimen targeting toll-like receptor-3 (TLR3), type-1 interferons (IFN) and the PGE2 system, selectively enhances CTL numbers but reduces regulatory T(reg) cells in TME, uniformly sensitizing tumors for the therapeutic effectiveness of PD-1 blockers and specialized dendritic cell vaccines (αDC1) in melanoma, colorectal cancer (CRC) and ovarian cancer (OvCa). We will now: 1) Determine local immunologic efficacy of systemically- or locally applied CKMs in cancer patients; 2) Identify the most effective ways of using CKM to enhance antitumor effects DC therapies and PD-1 blockade; and 3) Evaluate the clinical activity of the resulting therapies in PD-1-resistant cancer patients, and identify the most relevant TME correlates of clinical benefit. Project 1 Combinatorial adjuvants promote uniform and selective intratumoral CTL infiltration will test in a Phase IIa trial NCT03403634 whether systemic administration of CKM composed of rintatolimod (TLR3- ligand) IFNα and celecoxib promotes local CTL accumulation in TME of metastatic colorectal cancer (CRC). Magnitude of effects, tumor-selectivity (vs surrounding tissues) and mouse studies will guide the design of the second trial which will evaluate the clinical efficacy of sequential CMK/anti-PD-1 application in CRC patients. Project 2 Local immunotherapy corrects chemokine patterns in OvCa will complete the phase II portion of trial NCT02432378 to test the specificity of local CKM in attracting CTLs (rather than Tregs) to the TME of OvCa patients vaccinated with αDC1 loaded with own tumor cells (αDC1[tumor]) and identify “secondary” mechanisms or treatment resistance. The results will inform preclinical studies and the design of the second trial to determine the clinical activity of sequential treatment with DC[tumor]/CKM followed with PD-1 blockade. Project 3 Chemokine modulation to enhance CD8+ TIL recruitment and cross-priming in the TME is based on our latest observations (NCT01876212) of 57% objective response rate (ORR) to αDC1 vaccine targeting tumor blood vessels (αDC1[TBVA] in the 4 of 7 melanoma patients with primary PD1 resistance and 46% objective clinical benefit overall (6/13 patients). We will now perform phase II trial to evaluate the clinical activity of αDC1[DBVA] combined with systemic CKM (BB-IND16,704) in stage IV melanoma patients with primary PD1 resistance. Using correlative studies and mouse in vivo models, we will develop optimized and potentially simplified vaccines to complement CKM and PD-1 blockade for durable therapeutic benefit. Impact: We will test widely-applicable complementary approaches to promote selective entry of therapeutic CTLs into tumors. Since intratumoral CTL numbers predict survival and therapeutic advantage of checkpoint blockers in multiple cancer types, the results are likely to benefit a broad range of cancer patients.

修订后的 P01CA234212 测试了促进选择性 CTL 进入肿瘤微组织的新策略环境（TME）并使“冷”肿瘤对免疫疗法敏感。我们的临床前和早期临床数据证明针对 Toll 样受体 3 (TLR3) 1 型的趋化因子调节 (CKM) 方案干扰素 (IFN) 和 PGE2 系统，选择性增加 CTL 数量，但减少调节性 T (reg) 细胞在 TME 中，使肿瘤均匀敏化以发挥 PD-1 阻滞剂和专门药物的治疗效果用于治疗黑色素瘤、结直肠癌 (CRC) 和卵巢癌 (OvCa) 的树突状细胞疫苗 (αDC1)。我们现在将： 1) 确定癌症患者全身或局部应用 CKM 的局部免疫功效； 2）识别使用CKM增强抗肿瘤效果的最有效方法DC疗法和PD-1阻断；和 3) 评估由此产生的疗法在 PD-1 耐药癌症患者中的临床活性，并确定最有效的治疗方法相关的 TME 与临床获益相关。项目1 组合佐剂促进均匀选择性瘤内CTL浸润将进行测试在 IIa 期试验 NCT03403634 中，全身给药由 rintatolimod (TLR3- 配体）IFNα和塞来昔布促进转移性结直肠癌（CRC）TME中局部CTL积累。影响的大小、肿瘤选择性（相对于周围组织）和小鼠研究将指导设计第二项试验将评估序贯 CMK/抗 PD-1 应用在 CRC 患者中的临床疗效。项目 2 纠正 OvCa 趋化因子模式的局部免疫疗法将完成项目的 II 期部分试验 NCT02432378 测试局部 CKM 在吸引 CTL（而不是 Tregs）到 TME 中的特异性 OvCa 患者接种了装载有自身肿瘤细胞（αDC1[肿瘤]）的 αDC1 疫苗，并识别出“继发性” 机制或治疗抵抗。结果将为临床前研究和第二个研究的设计提供信息试验以确定 DC[肿瘤]/CKM 序贯治疗随后 PD-1 阻断的临床活性。项目 3 趋化因子调节可增强 TME 中 CD8+ TIL 的募集和交叉引发基于我们对 αDC1 疫苗的 57% 客观缓解率 (ORR) 的最新观察结果 (NCT01876212) 靶向肿瘤血管（7 名具有原发性 PD1 耐药性的黑色素瘤患者中的 4 名是 αDC1[TBVA] 总体客观临床获益率为 46%（6/13 名患者）。我们现在将进行 II 期试验来评估临床 IV 期黑色素瘤患者中 αDC1[DBVA] 联合全身 CKM (BB-IND16,704) 的活性原发性PD1抵抗。利用相关研究和小鼠体内模型，我们将开发优化和可能简化的疫苗可以补充 CKM 和 PD-1 阻断，从而获得持久的治疗效果。影响：我们将测试广泛适用的补充方法，以促进治疗的选择性进入 CTL 进入肿瘤。由于肿瘤内 CTL 数量可以预测生存率和检查点的治疗优势多种癌症类型的阻滞剂，其结果可能使广泛的癌症患者受益。