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:AbbreviationsAndrogen AntagonistsAndrogen ReceptorAndrogensAngiogenesis InhibitorsAnimal ModelAntigen TargetingAntigensApoptosisAttentionAutologousAutologous Dendritic CellsBiological AssayBloodBlood VesselsBlood flowCD8-Positive T-LymphocytesCD8B1 geneCellsClear cell renal cell carcinomaClinicClinicalClinical TrialsCombination immunotherapyCross-PrimingDendritic CellsDendritic cell tumorDevelopmentDiagnosisDisease ProgressionDoseEnhancing LesionEpitopesExcisionExhibitsFemaleFosteringFutureGenderGender IssuesGenerationsGenetic TranscriptionGonadal Steroid HormonesHLA-A2 AntigenHumanHypoxiaImmuneImmune checkpoint inhibitorImmunityImmunologicsImmunotherapyIn SituInbred BALB C MiceIncidenceInflammationInflammatoryIntercellular FluidInterferon Type IIInterleukin-2InterruptionInterventionLymphocyteLymphoidMaintenanceMalignant NeoplasmsMediatingMusNeoplasms in Vascular TissueOperative Surgical ProceduresOralPatientsPeptide VaccinesPeptidesPerfusionPericytesPhasePhase II Clinical TrialsPhenotypePrognosisReceptor SignalingRenal Cell CarcinomaResistanceRoleSiteSterilityStructureSystems BiologyT cell responseT-LymphocyteTestingTherapeuticTherapeutic InterventionTranslationsTreatment EfficacyTumor ImmunityTumor TissueTumor-infiltrating immune cellsVaccinationVaccine AntigenVaccinesVascular Endothelial Cellantagonistbasebiosignaturecytokinedesigndimorphismeffective therapyenzyme linked immunospot assayexhaustfitnessimmune checkpoint blockadeimmunogenicimmunogenic cell deathimmunogenicityimprovedin vivoinhibitorlymphoid organmalemelanomanecrotic tissuenovelpatient responsepressureprognostic indicatorreceptorrecruitresponsesexual dimorphismtertiary lymphoid organtherapy outcometreatment responsetumortumor microenvironmenttumor progressionvaccine efficacyvaccine 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
尽管肾细胞癌通常被归类为免疫原性肿瘤,但最近的侧写研究表明
CD8+TIL在这种类型的癌症中的存在是预后不良的指标。这些发现强调了
在肿瘤微环境中评价免疫环境/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应答的可能影响
到介入性治疗。事实上,如果人们转而考虑CD8+T细胞和成熟DC的有组织集群-
LAMP+树突状细胞(DC)在肿瘤的三级淋巴结构(TLS)内,这些淋巴“器官”是
肾癌患者总存活率/PFS的阳性预后指标。与肿瘤相关的TLS已经被
建议作为免疫“绿洲”,为表现出较少耗尽表型的淋巴细胞渗透,以及
作为原位DC介导的多种治疗性CD8+T细胞库交叉启动的位点。我们有
最近研究表明,接种肿瘤相关血管抗原(TBVA)可导致血管
正常化(VN;即血管修剪,减少血管渗漏/缺氧/间质液体压)和De
以介入性疫苗为基础的肿瘤内TLS在小鼠和人体内的新发展
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果。
深刻的性别/性二态,女性(或被阉割的男性)对完整男性的反应率更高,
这表明性激素及其受体具有调节作用。我们的中心假设是:i.)
联合免疫治疗促进肾癌VN将促进TLS的发展和AFP的产生
具有广泛反应性的CD8+T细胞治疗谱系,表现出卓越的“适合性”和抗肿瘤疗效,以及ii.)
联合应用雄激素合成/AR可避免疫苗接种引起的性别二态反应
对抗者。考虑到慢性肾细胞癌的男性和女性发病率为2:1,这些后一项研究预计将显著
扩大以TBVA为靶点的肾癌疫苗的治疗作用。我们将首先进行一次探索性
以α+口服小剂量为靶点的自体TBVA Dc1/多肽疫苗的临床试验
卡波赞替尼对新近确诊的原发肿瘤患者VN、TLS形成和肿瘤浸润性T细胞适合性的影响
CcRCC在计划手术切除(目标1)之前,然后进行动物模型以验证假说
这是我。)在小鼠肾细胞癌(RencA,RENCA.VHL-/-)肿瘤中能够促进VN的药物将与
针对RCC和/或TBVA抗原的疫苗+/-检查点阻断促进TLS的发展,
改善肿瘤浸润性T细胞(TIL)的适合性,扩大TIL谱系和卓越的治疗效益(AIM
2)和ii.)能够阻断雄激素合成/雄激素受体信号转导的药物将得到改善
VN诱导免疫疗法对BALB/c雄性/雌性小鼠肾细胞癌的治疗效果(目标3)。
项目成果
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JODI Kathleen MARANCHIE其他文献
JODI Kathleen MARANCHIE的其他文献
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{{ truncateString('JODI Kathleen MARANCHIE', 18)}}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:
10295913 - 财政年份:2021
- 资助金额:
$ 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:
10682463 - 财政年份:2021
- 资助金额:
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Virtual Histology of the Bladder Wall for Bladder Cancer Staging
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10044470 - 财政年份:2020
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