权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10295913
负责人：
JODI Kathleen MARANCHIE
金额：
$ 45.67万
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/10295913
关键词：
Abbreviations Androgen Antagonists 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 Clear cell renal cell carcinoma Clinic Clinical Clinical Trials Combination immunotherapy Cross-Priming Dendritic Cells Dendritic cell tumor Development Diagnosis Disease Progression Dose Enhancing Lesion 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 Inflammation Inflammatory Intercellular Fluid Interferon Type II Interleukin-2 Interruption Intervention Lymphocyte Lymphoid Maintenance 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 Prognostic Marker Receptor Signaling Renal Cell Carcinoma Resistance Role Site Sterility Structure Systems Biology T cell response T-Lymphocyte Testing Therapeutic Therapeutic Intervention Translations Treatment Efficacy Tumor Immunity Tumor Tissue Tumor-infiltrating immune cells Vaccination Vaccine Antigen Vaccines Vascular Endothelial Cell base biosignature cytokine design dimorphism effective therapy enzyme linked immunospot assay exhaust fitness immune checkpoint blockade immunogenic immunogenic cell death immunogenicity improved in vivo inhibitor/antagonist lymphoid organ male melanoma necrotic tissue novel patient response pressure receptor recruit response sexual dimorphism 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).

摘要尽管RCC通常被归类为免疫原性肿瘤，但最近的分析研究表明，在这种形式的癌症中存在CD 8 + TIL是预后不良的指标。这些发现强调，在肿瘤微环境中了解免疫背景/免疫细胞网络的重要性，解释肿瘤免疫的运作状态及其对疾病进展和反应的可能影响介入治疗事实上，如果考虑到有组织的CD 8 + T细胞和成熟的DC- 肿瘤中三级淋巴样结构（TLS）内的LAMP+树突状细胞（DC），这些淋巴样“器官” RCC患者总生存期/PFS的阳性预后指标。肿瘤相关性TLS已被建议用作表现出较少耗尽表型的浸润淋巴细胞的免疫“绿洲”，作为原位DC介导的交叉致敏多样化治疗性CD 8 + T细胞库的位点。我们有最近表明，针对肿瘤相关血管抗原（TBVA）的疫苗接种导致血管正常化（VN;即血管修整，减少血管渗漏/缺氧/间质液压力）和去血管化。小鼠和人类肿瘤中TLS的新生发展对基于疫苗的干预性治疗有反应免疫疗法。值得注意的是，我们还观察到这些疫苗的抗肿瘤功效表现出深刻的性别/性二态性，女性（或去势男性）的反应率高于完整男性，这表明性类固醇及其受体具有调节作用。我们的主要假设是：i.）在RCC中促进VN的联合免疫疗法将促进TLS的发展和表现出上级“适应性”和抗肿瘤功效的广泛反应性治疗性CD 8 + T细胞库，和ii.）雄激素合成/AR联合给药可避免对疫苗接种的性别二型反应对手。考虑到ccRCC的男性：女性发病率为2：1，预计这些后续研究将显着增加扩大TBVA靶向疫苗对RCC的治疗效用。我们将首先进行一次探索性的确定靶向TBVA +口服低剂量自体α DC 1/肽疫苗的影响的临床试验卡博替尼对最近诊断的原发性肝癌患者中VN、TLS形成和肿瘤浸润性T细胞适应性的影响 ccRCC在计划的手术切除之前（目标1），然后在追求动物模型以测试假设之前 I.）能够在鼠RCC（RENCA，RENCA，VHL-/-）肿瘤中促进VN的药剂将与靶向RCC和/或TBVA抗原的疫苗+/-检查点封锁促进TLS的发展，改善的肿瘤浸润性T细胞（TIL）适应性、扩大的TIL库和优越的上级治疗益处（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诱导免疫疗法在携带RCC肿瘤的雄性/雌性BALB/c小鼠中的治疗效果（目的3）。