Vaccine Targeting of RCC Blood Vessels to Promote TME Normalization and Enhance TIL Recruitment

靶向 RCC 血管的疫苗促进 TME 正常化并增强 TIL 招募

基本信息

批准号：
10682463
负责人：
JODI Kathleen MARANCHIE
金额：
$ 45.21万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10682463
关键词：
Abbreviations Androgen Receptor Androgens Angiogenesis Inhibitors Animal Model Antigen Targeting Antigens Apoptosis Attention Autologous Autologous Dendritic Cells Biological Assay Blood Blood Vessels Blood flow CD8-Positive T-Lymphocytes CD8B1 gene Cells Classification Clear cell renal cell carcinoma Clinic Clinical Clinical Trials Combination immunotherapy Cross-Priming Dendritic Cells Development Diagnosis Disease Progression Dose Epitopes Excision Exhibits Female Fostering Future Gender Gender Issues Generations Genetic Transcription Gonadal Steroid Hormones HLA-A2 Antigen Human Hypoxia Immune Immune checkpoint inhibitor Immunity Immunologics Immunotherapy In Situ Inbred BALB C Mice Incidence Infiltration Inflammation Inflammatory Intercellular Fluid Interferon Type II Interleukin-2 Interruption Intervention Lymphocyte Lymphoid Maintenance Male Castration Malignant Neoplasms Mediating Mus Neoplasms in Vascular Tissue Operative Surgical Procedures Oral Patients Peptide Vaccines Peptides Perfusion Pericytes Phase Phase II Clinical Trials Phenotype Prognosis Receptor Signaling Renal Cell Carcinoma Resistance Role Site Sterility Structure Systems Biology T cell infiltration T cell receptor repertoire sequencing T cell response T-Lymphocyte Testing Therapeutic Therapeutic Intervention Translations Treatment Efficacy Tumor Expansion Tumor Immunity Tumor Tissue Vaccination Vaccine Antigen Vaccines Vascular Endothelial Cell antagonist biosignature cancer infiltrating T cells cytokine design dimorphism effective therapy enzyme linked immunospot assay exhaust fitness immune cell infiltrate immune checkpoint blockade immunogenic immunogenic cell death immunogenicity improved in vivo inhibitor lymphoid organ male melanoma necrotic tissue novel patient response pressure prognostic indicator receptor recruit response sexual dimorphism synergism tertiary lymphoid organ therapy outcome treatment response tumor tumor microenvironment tumor progression vaccine efficacy vaccine immunotherapy

项目摘要

ABSTRACT Although RCC is typically classified as an immunogenic tumor, recent profiling studies instead suggest that presence of CD8+ TIL in this form of cancer is an indicator of poor prognosis. These findings emphasize the importance of appreciating immune context/immune cell networking in the tumor microenvironment when interpreting the operational status of tumor immunity and its likely impact on disease progression and response to interventional therapy. Indeed, if one instead considers organized clusters of CD8+ T cells and mature DC- LAMP+ dendritic cells (DC) within tertiary lymphoid structures (TLS) in tumors, these lymphoid “organs” are positive prognostic indicators for overall survival/PFS in RCC patients. Tumor-associated TLS have been suggested to serve as an immune “oasis” for infiltrating lymphocytes exhibiting less-exhausted phenotypes, and as sites for in situ DC-mediated cross-priming of a diversified therapeutic CD8+ T cell repertoire. We have recently shown that vaccination against tumor-associated blood vessel antigens (TBVA) results in vascular normalization (VN; i.e. vascular trimming, reduced vascular leak/hypoxia/interstitial fluid pressure) and the de novo development of TLS within tumors in mice and humans responding to interventional vaccine-based immunotherapy. Remarkably, we have also observed that the anti-tumor efficacy of these vaccines exhibits profound gender/sexual dimorphism, with higher response rates in females (or castrated males) vs. intact males, suggesting a regulatory role for sex steroids and their receptors. Our central hypotheses are that: i.) combination immunotherapy promoting VN in RCC will enhance TLS development and the generation of a broadly-reactive therapeutic CD8+ T cell repertoire exhibiting superior “fitness” and anti-tumor efficacy, and ii.) gender dimorphic response to vaccination can be circumvented by co-administration of androgen synthesis/AR antagonists. Given a 2:1 male:female incidence of ccRCC, these latter studies are expected to dramatically expand the therapeutic utility of TBVA-targeted vaccines against RCC. We will initially perform an exploratory clinical trial to determine the impact of an autologous αDC1/peptide vaccine targeting TBVA + oral low-dose cabozantinib on VN, TLS formation and tumor-infiltrating T cell fitness in patients with recently-diagnosed primary ccRCC prior to planned surgical resection (Aim 1), before then pursuing animal models to test the hypotheses that i.) agents capable of promoting VN in murine RCC (RENCA, RENCA.VHL-/-) tumors will synergize with vaccines targeting RCC and/or TBVA antigens +/- checkpoint blockade in promoting the development of TLS, improved tumor-infiltrating T cell (TIL) fitness, an expanded TIL repertoire and superior therapeutic benefit (Aim 2) and ii.) agents capable of interrupting androgen synthesis/androgen receptor-signaling will improve therapeutic efficacy of VN-inducing immunotherapies in male/female BALB/c mice bearing RCC tumors (Aim 3).

抽象的尽管肾细胞癌通常被归类为免疫原性肿瘤，但最近的分析研究表明， CD8+ TIL 在这种形式的癌症中的存在是预后不良的一个指标。了解肿瘤微环境中免疫背景/免疫细胞网络的重要性解释肿瘤免疫的运行状态及其对疾病进展和反应的可能影响事实上，如果我们考虑的是有组织的 CD8+ T 细胞簇和成熟的 DC- 细胞。肿瘤中三级淋巴结构 (TLS) 内的 LAMP+ 树突状细胞 (DC)，这些淋巴“器官”是 RCC 患者的总生存率/PFS 具有积极的预后指标。建议作为表现出较少耗尽表型的浸润淋巴细胞的免疫“绿洲”，以及作为原位 DC 介导的多样化治疗性 CD8+ T 细胞库交叉启动的位点。最近表明，针对肿瘤相关血管抗原（TBVA）的疫苗接种会导致血管正常化（VN；即血管修剪、减少血管渗漏/缺氧/间质液压力）和去小鼠和人类肿瘤内 TLS 的新开发对基于介入疫苗的反应值得注意的是，我们还观察到这些疫苗具有抗肿瘤功效。广泛的性别/性二态性，女性（或阉割的男性）与完整的男性相比，反应率更高，表明性类固醇及其受体的调节作用是：i.) 促进 RCC 中 VN 的联合免疫疗法将促进 TLS 的发展和生成具有广泛反应性的治疗性 CD8+ T 细胞库，表现出卓越的“适应性”和抗肿瘤功效，ii.) 通过联合施用雄激素合成/AR可以避免对疫苗接种的性别二态性反应考虑到 ccRCC 的男性：女性发病率为 2:1，后面这些研究预计将显着改善。扩大 TBVA 靶向疫苗对 RCC 的治疗效用我们将首先进行一项探索性研究。确定针对 TBVA + 口服低剂量的自体 αDC1/肽疫苗的影响的临床试验卡博替尼对最近诊断的原发性肿瘤患者的 VN、TLS 形成和肿瘤浸润 T 细胞适应性的影响在计划的手术切除（目标 1）之前进行 ccRCC，然后建立动物模型来检验假设 i.) 能够在鼠肾细胞癌 (RENCA, RENCA.VHL-/-) 肿瘤中促进 VN 的药物将与针对 RCC 和/或 TBVA 抗原的疫苗 +/- 检查点阻断以促进 TLS 的发展，改善肿瘤浸润 T 细胞 (TIL) 适应性、扩展 TIL 库和卓越的治疗效果（Aim 2) 和 ii.) 能够中断雄激素合成/雄激素受体信号传导的药物将改善 VN 诱导免疫疗法对患有 RCC 肿瘤的雄性/雌性 BALB/c 小鼠的治疗效果（目标 3）。