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测试了新型策略，以促进选择性CTL进入肿瘤微型 - 环境（TME）和对免疫疗法的敏感“冷”肿瘤。我们的临床前和早期临床数据证明趋化因子调节（CKM）方案靶向类似收费的受体-3（TLR3），Type-1 干扰素（IFN）和PGE2系统有选择地增强CTL数字，但减少了调节t（reg）细胞在TME中，对PD-1阻滞剂和专业的治疗有效性均匀敏感黑色素瘤，结直肠癌（CRC）和卵巢癌（OVCA）中的树突状细胞疫苗（αDC1）。我们现在将： 1）确定癌症患者全身或局部应用CKM的局部免疫效率； 2）识别使用CKM增强抗肿瘤效应直流疗法和PD-1阻滞的最有效方法； 3）评估PD-1耐药性癌症患者所得疗法的临床活性，并确定最多相关的TME临床益处相关。项目1组合调节器促进统一和选择性的肿瘤内CTL浸润将测试在IIA期试验中，NCT03403634是由Rintatolimod组成的全身给药（TLR3-- 配体）IFNα和Celecoxib促进了转移性结直肠癌（CRC）TME的局部CTL积累。效应的大小，肿瘤选择性（与周围组织）和小鼠研究将指导的设计第二次试验将评估CRC患者中顺序CMK/抗PD-1的临床效率。项目2局部免疫疗法纠正OVCA中的趋化因子模式将完成的II期部分试验NCT02432378测试局部CKM在吸引CTL（而不是Tregs）中的特异性用αDC1接种的OVCA患者，该患者载有自身肿瘤细胞（αDC1[肿瘤]），并鉴定“次要” 机制或耐药性。结果将为临床前研究和第二个设计试验以确定DC [肿瘤]/CKM顺序治疗的临床活性，然后在PD-1阻断中进行。项目3趋化因子调制以增强CD8+ TIL募集和TME中的交叉播种基于我们对αDC1疫苗的最新观察结果（NCT01876212）的目标响应率（ORR）靶向肿瘤血管（αDC1[TBVA]的7例黑色素瘤患者中的4例总体46％的客观临床益处（6/13例）。现在，我们将进行II期试验以评估临床 αDC1[DBVA]的活性与全身性CKM（BB-IND16,704）在IV期黑色素瘤患者中主要PD1电阻。使用相关研究和在体内模型中的鼠标，我们将开发优化和有可能简化的疫苗补充CKM和PD-1阻滞以获得持久的治疗益处。影响：我们将测试广泛适用的完成方法，以促进选择性治疗的选择性进入 CTL进入肿瘤。由于肿瘤内CTL数量可以预测检查点的生存和治疗优势多种癌症类型的阻滞剂，结果可能会使广泛的癌症患者受益。