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:
- 金额:$ 45.21万
- 依托单位:
- 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:
- 关键词:
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)。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
JODI Kathleen MARA...的其他基金
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
- 批准号:1029591310295913
- 财政年份:2021
- 资助金额:$ 45.21万$ 45.21万
- 项目类别:
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
- 批准号:1068246310682463
- 财政年份:2021
- 资助金额:$ 45.21万$ 45.21万
- 项目类别:
Virtual Histology of the Bladder Wall for Bladder Cancer Staging
用于膀胱癌分期的膀胱壁虚拟组织学
- 批准号:1004447010044470
- 财政年份:2020
- 资助金额:$ 45.21万$ 45.21万
- 项目类别:
Imapct of Renox on HIF-alpha in Renal Cancer
Renox 对肾癌 HIF-α 的影响
- 批准号:72535567253556
- 财政年份:2003
- 资助金额:$ 45.21万$ 45.21万
- 项目类别:
Imapct of Renox on HIF-alpha in Renal Cancer
Renox 对肾癌 HIF-α 的影响
- 批准号:68992826899282
- 财政年份:2003
- 资助金额:$ 45.21万$ 45.21万
- 项目类别:
Impact of Renox on HIF-alpha in Renal Cancer
Renox 对肾癌 HIF-α 的影响
- 批准号:72855797285579
- 财政年份:2003
- 资助金额:$ 45.21万$ 45.21万
- 项目类别:
Impact of Renox on HIF-alpha in Renal Cancer
Renox 对肾癌 HIF-α 的影响
- 批准号:66752346675234
- 财政年份:2003
- 资助金额:$ 45.21万$ 45.21万
- 项目类别:
Imapct of Renox on HIF-alpha in Renal Cancer
Renox 对肾癌 HIF-α 的影响
- 批准号:70952587095258
- 财政年份:2003
- 资助金额:$ 45.21万$ 45.21万
- 项目类别:
Imapct of Renox on HIF-alpha in Renal Cancer
Renox 对肾癌 HIF-α 的影响
- 批准号:67880626788062
- 财政年份:2003
- 资助金额:$ 45.21万$ 45.21万
- 项目类别:
相似国自然基金
靶向Sub-LBP的新型雄激素受体拮抗剂的发现及其抗前列腺癌活性研究
- 批准号:82304381
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
二代雄激素受体拮抗剂激活非经典转录途径诱导前列腺癌耐药的分子机制及利用CRISPR-Cas13干预耐药的研究
- 批准号:
- 批准年份:2022
- 资助金额:30 万元
- 项目类别:青年科学基金项目
二代雄激素受体拮抗剂激活非经典转录途径诱导前列腺癌耐药的分子机制及利用CRISPR-Cas13干预耐药的研究
- 批准号:82202922
- 批准年份:2022
- 资助金额:30.00 万元
- 项目类别:青年科学基金项目
基于干预ARfl/ARv7异源二聚体形成的新型抗前列腺癌候选药物LLU-206的作用机制研究
- 批准号:81903656
- 批准年份:2019
- 资助金额:21.0 万元
- 项目类别:青年科学基金项目
基于雷公藤单体雷酚内酯发展治疗去势抵抗前列腺癌(CRPC)的新策略
- 批准号:81672559
- 批准年份:2016
- 资助金额:53.0 万元
- 项目类别:面上项目
相似海外基金
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
- 批准号:1029591310295913
- 财政年份:2021
- 资助金额:$ 45.21万$ 45.21万
- 项目类别:
Small-Molecule Disruptors of the Nuclear Hormone Receptor/Coactivator Interaction
核激素受体/共激活剂相互作用的小分子干扰剂
- 批准号:76731787673178
- 财政年份:2009
- 资助金额:$ 45.21万$ 45.21万
- 项目类别:
Dynamic, Structure Driven Fragment Based Design of Selective Androgen Modulators
基于动态结构驱动片段的选择性雄激素调制器设计
- 批准号:73943117394311
- 财政年份:2008
- 资助金额:$ 45.21万$ 45.21万
- 项目类别: