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：
10491108
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/10491108
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 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 antagonist 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 lymphoid organ male melanoma necrotic tissue novel patient response pressure prognostic indicator 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).

抽象的尽管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，CD8+ TIL的存在是预后不良的指标。这些发现强调了在肿瘤微环境中欣赏免疫膜片/免疫细胞网络的重要性解释肿瘤免疫学的操作状态及其对疾病进展和反应的可能影响进行介入疗法。确实，如果一个人考虑了CD8+ T细胞的有组织簇和成熟的DC- 肿瘤中的第三纪淋巴样结构（TLS）内的灯+树突状细胞（DC），这些淋巴样“器官”是 RCC患者的总生存/PF的阳性预后指标。肿瘤相关的TLS已建议用作浸润淋巴细胞的免疫“绿洲”，表现出较少的表型，并且作为原位DC介导的多样化治疗CD8+ T细胞库的交叉杂化的位置。我们有最近表明，针对肿瘤相关血管抗原（TBVA）的疫苗导致血管归一化（VN；即血管修剪，减少血管泄漏/缺氧/间质流体压力）和DE 小鼠和人类肿瘤中TLS的Novo开发，对介入疫苗的反应免疫疗法。值得注意的是，我们还观察到这些疫苗的抗肿瘤效率表现出强烈的性别/性二态性，女性（或cast割男性）与完整男性的反应率更高，暗示性别立体及其接收器的调节作用。我们的中心假设是：i。） RCC中促进VN的联合疗法将增强TLS的发展和生成广泛反应性的治疗性CD8+ T细胞库具有出色的“适应性”和抗肿瘤效率，以及II。性别二态对疫苗接种的反应可以通过雄激素合成/AR的共同给药来规避对手。给定2：1男性：CCRCC的女性事件，这些后来的研究有望急剧扩展针对RCC的TBVA靶向疫苗的治疗效用。我们最初将进行探索性临床试验确定靶向TBVA +口服低剂量的自体αDC1/肽疫苗的影响最近诊断为原发性诊断的患者的VN，TLS形成和肿瘤浸润T细胞适应性的Cabozantinib 在计划的手术切除（AIM 1）之前，CCRC（AIM 1），然后追求动物模型来检验假设 i。针对RCC和/或TBVA抗原的疫苗+/-检查点阻滞了TLS的发展，改善了肿瘤浸润的T细胞（TIL）适应性，扩大的截止曲目和优质治疗益处（AIM 2）和II。）能够中断雄激素合成/雄激素受体信号的药物会改善 VN诱导的雄性/雌性BALB/C小鼠的免疫疗法的治疗效率（AIM 3）。