Project 3: Chemokine modulation in TME for enhanced TLS formation and cross-priming/ recruitment of therapeutic CD8+ TILs

项目 3：TME 中的趋化因子调节，以增强 TLS 形成和治疗性 CD8 TIL 的交叉引发/招募

• 批准号: 10362702
• 负责人: Walter J. Storkus
• 金额: $ 43.34万
• 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/10362702
• 关键词: Aftercare; Animal Model; Antigens; Autologous; Biopsy; Blood; Blood Vessels; CCL19 gene; CCL21 gene; CCL22 gene; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCL9 gene; Cells; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Combination immunotherapy; Combined Vaccines; Common Neoplasm; Cross-Priming; Dasatinib; Data; Dendritic Cells; Development; Epitope spreading; Equilibrium; Evaluable Disease; Exhibits; HLA-A2 Antigen; Harvest; Immune; Immune checkpoint inhibitor; Immunologics; Immunotherapy; Inflammatory; Interferon alpha; Interferons; Intervention; Ligands; Link; Lymphoid; MC38; Malignant Neoplasms; Modeling; Molecular; Molecular Mechanisms of Action; Monitor; Mus; Myeloid-derived suppressor cells; Natural Killer Cells; Neoplasms in Vascular Tissue; PD-1 blockade; PD-1/PD-L1; Pathway interactions; Patients; Peptide Vaccines; Peptides; Phase I/II Trial; Play; Production; Progression-Free Survivals; Prospective Studies; Protocols documentation; RANTES; Refractory; Regimen; Regulatory T-Lymphocyte; Resistance; Role; Stromal Cell-Derived Factor 1; Structure; Suppressor-Effector T-Lymphocytes; System; T cell infiltration; T cell response; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Therapeutic Intervention; Tissues; Treatment Efficacy; Up-Regulation; Vaccination; Vaccines; antagonist; anti-PD-1; anti-PD-L1; celecoxib; chemokine; clinical efficacy; clinically relevant; comparative; design; experimental study; immune cell infiltrate; immune checkpoint blockade; improved; in situ vaccine; melanoma; novel; peptide based vaccine; peptide vaccination; peripheral blood; phase 2 study; programmed cell death protein 1; prospective; recruit; response; synergism; tertiary lymphoid organ; tool; treatment site; tumor; tumor microenvironment; tumor progression

ABSTRACT Chemokines (CK) play critical roles in the recruitment of immune cells into cancer tissues. Progressing tumors are commonly characterized by local production of regulatory chemokines (CKs) and suppressor cells, while production of pro-inflammatory CKs recruits protective CTLs and Th1 cells, dendritic cells (DC) and NK cells into the tumor microenvironment (TME) in association with effective (immuno)therapeutic intervention. We have recently shown that a combination vaccine targeting tumor vascular antigens (TVA) promotes specific CD8+ T cell responses and the coordinate upregulation of stromal CCL5/CXCL9-11 production and therapeutic T cell infiltration, and reduction in CCL22/CXCL12 production and MDSC/Treg content in the TME. Treatment also promotes de novo production of CCR7-ligand CKs CCL19/CCL21 in the TME, and the development of tertiary lymphoid-like structures (TLS). Remarkably, an autologous αDC1/TVA peptide-based vaccine administered with dasatinib to immune checkpoint blockade (ICB)-refractory patients with advanced-stage melanoma (NCT01876212) resulted in objective clinical benefit in 6 of 13 (46%) evaluable patients overall, including 4 of 7 (57%) patients exhibiting primary resistance to anti-PD1 blockade therapy. TCRBseq analyses revealed increased TCR convergence (i.e. immune focus) in the therapy-induced TIL repertoire in advance of objective clinical response. Furthermore, clinical responders exhibited unique TIL clonotypes post-treatment that were not detectable in blood, supporting the TME as a relevant site for treatment-dependent T cell cross-priming and “epitope spreading”. Since new preliminary data in murine B16 melanoma models suggests that therapeutic efficacy of αDC1/TBVA-based vaccines is superior when combined with the Project 1-developed CK modulation (CKM) regimen vs. dasatinib, Project 3, we will test the hypothesis that therapeutic benefits resulting from αDC1/vascular peptide-based immunotherapy in immune checkpoint inhibitor (ICI)-refractory, advanced-stage melanoma patients will be increased when combined with chemokine-modulating regimens (including CKM), Specifically, we will perform a Phase I/II trial of Type-1-polarized dendritic cell (αDC1)/TVA peptide vaccination in combination with tumor-selective chemokine modulation (CKM: Interferon-α2b, Rintatolimod and Celecoxib) in advanced-stage HLA-A2+ melanoma patients with primary PD-1/PD-L1 resistance (Aim 1) and analyze the on-treatment changes in TME and blood of patients to determine clinically-relevant changes in immunological analytes (Aim 2). Animal modeling will then be performed to determine the role of vaccine format in the therapeutic efficacy of combination CKM-based immunotherapy +/- immune regulatory antagonists (Aim 3).

抽象的 趋化因子（CK）在免疫细胞募集到癌症组织中起关键作用。 通常以局部生产调节性趋化因子（CK）和抑制细胞的特征，而 促炎CKS的产生招募保护性CTL和TH1细胞（树突状细胞（DC）和NK细胞进入 肿瘤微环境（TME）与有效的（免疫）治疗干预 最近表明，组合疫苗肿瘤血管抗原（TVA）促进了特定的CD8+ T 细胞反应和基于基质CCL5/CXCL9-11产生和治疗T细胞的协调上调 TME中的CCL22/CXCL12产生和MDSC/Treg含量中的浸润和修复。 促进TME中CCR7-Ligand Cks CCL19/CCL21的从头产生 淋巴样结构（TLS）。 达沙替尼至免疫检查点阻滞（ICB） - 晚期黑色素瘤的饮食患者 （NCT01876212）在13个（46％）可评估的患者中有6例带来了客观的临床益处 （57％）对抗PD1封锁治疗的主要抵抗力的患者。 提高TCR收敛性（即免疫焦点）在疗程中的TIL TILTOIRE中的提高 临床反应。 在血液中可检测，支持TME作为依然部位，用于治疗依赖性T细胞交叉染色和 “表位扩散”，因为鼠类B16模型中的新初步数据表明那是那个 与项目1开发的CK调制时，基于αDC1/TBVA的疫苗的疗效优越 （CKM）方案与达萨替尼（Dasatinib），项目3，我们将检验以下假设。 免疫检查点抑制剂（ICI）的αDC1/基于血管肽的免疫疗法 - 反应，晚期 当与趋化因子调节方案（包括CKM）合并时，黑色素瘤患者将增加。 具体而言，我们将对1级偏振树状细胞（αDC1）/TVA肽疫苗的I/II期试验进行I/II期试验。 结合肿瘤选择性趋化因子调节（CKM：干扰素-α2B，Rintatolimod和Celecoxib） 在初级PD-1/PD-L1耐药性的高级HLA-A2+黑色素瘤患者中（AIM 1）并分析您 在TME和患者血液中进行的治疗变化，以确定免疫学与临床相关的变化 分析物（AIM 2）。 基于CKM的免疫疗法+/-免疫调节拮抗剂的治疗功效（AIM 3）。