Immunotherapy Modeling in Organoids Co-preserving Tumor and Infiltrating Immune Compartments

共保存肿瘤和浸润免疫区室的类器官的免疫治疗模型

基本信息

  • 批准号:
    10374163
  • 负责人:
  • 金额:
    $ 64.36万
  • 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:
    2021-03-17 至 2026-02-28
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY The immune system remarkably distinguishes between self and non-self/self-aberrant antigens, affording exquisite anti-tumor specificity and inhibition of tumorigenesis. However, tumor immunosurveillance is unfortunately opposed by tumor cell evasion of the immune response. Immune checkpoint blockade (ICB) targeting PD-1, PD-L1, CD40 and others, as well as adoptive cell transfer (CAR-T, bulk TILs) favorably modulate this equilibrium for therapeutic benefit. However, response rates are often incomplete, progressive disease is common, and predictive biomarkers are suboptimal. The development of next-generation immunotherapies has been hindered by a lack of in vitro models that functionally recapitulate syngeneic interactions between tumor and infiltrating immune cells. In response, we have developed organoid methods that culture primary human tumor biopsies together with their infiltrating immune components as a cohesive unit without reconstitution. These “patient-derived tumor organoids” (PDO) preserve tumor cells alongside endogenous T, B, NK cells and macrophages, robustly recapitulate the T cell receptor clonotype repertoire of the original tumor, and crucially, manifest tumor-infiltrating lymphocyte (TIL) expansion, activation and tumor cell killing in response to anti-PD-1/PD-L1 therapeutic antibodies (Cell, 2018). The PDO system thus represents a holistic organoid model of human tumor-immune interactions. Here, we leverage the PDO technique to investigate immunotherapeutic mechanisms and treatments in PD-1-responsive cutaneous squamous cell carcinoma (cSCC) and melanoma, exploiting pre- and post-treatment human biopsies and mouse models. Aim 1 hypothesizes that checkpoint inhibition induces a complex and sequential network response involving immune-tumor and immune-immune crosstalk. Thus, Aim 1 employs the ability to perform serial time-course sampling of PDOs to define a single cell RNA-seq network cellular crosstalk model of the early anti-PD-1-stimulated anti-tumor immune response over multiple acute time points typically inaccessible to clinical biopsies performed after months. Importantly, comparison of this immune propagation in responding versus non-responding mouse and human organoids will define nodal points conferring resistance. Aim 2 improves bulk TIL adoptive transfer immunotherapy by using PDOs as living bioreactors to enrich tumor-reactive mouse and human melanoma TILs by anti-PD-1 checkpoint inhibition, followed by testing of enhanced anti-tumor activity in vitro and in vivo. Lastly, Aim 3 performs a co-treatment trial comparing anti-PD-1 responses of pre-treatment biopsy cSCC PDOs to clinical outcomes. Further, post- treatment biopsy PDOs are re-challenged with anti-PD-1 and a novel agent inactivating PD-1 by dephosphorylation. We thus utilize the holistic PDO model preserving endogenous tumor epithelial and immune components en bloc to investigate and improve cancer immunotherapy via our team of Calvin Kuo (organoids), Mark Davis and Chris Garcia (tumor immunology) and Anne Chang and Dimitri Colevas (cSCC clinicians).
项目摘要 免疫系统明显区分自我和非自我/自我灭绝的抗原,可提供 精致的抗肿瘤​​特异性和抑制肿瘤发生。但是,肿瘤免疫监视是 不幸的是,免疫反应的肿瘤细胞演变反对。免疫检查点封锁(ICB) 靶向PD-1,PD-L1,CD40等,以及自适应细胞转移(CAR-T,散装TIL)经常调节 这对治疗益处的同等效果。但是,回应率通常不完整,进行性疾病是 常见和预测生物标志物是次优的。 缺乏体外模型阻碍了下一代免疫疗法的发展 这在功能上概括了肿瘤与浸润的免疫细胞之间的合成性相互作用。作为回应, 我们开发了培养原发性人类肿瘤活检及其浸润的器官方法 免疫组件作为无凝结单元而无需重新构成的单位。这些“患者衍生的肿瘤器官”(PDO) 与内源性T,B,NK细胞和巨噬细胞一起保存肿瘤细胞,可稳固地概括T细胞 原始肿瘤的受体克隆型曲目,并完全表现出肿瘤浸润淋巴细胞(TIL) 响应抗PD-1/PD-L1治疗抗体的膨胀,激活和肿瘤细胞杀死(Cell,2018)。 因此,PDO系统代表了人类肿瘤免疫相互作用的整体器官模型。 在这里,我们利用PDO技术来研究免疫治疗机制和 PD-1响应性皮肤鳞状细胞癌(CSCC)和黑色素瘤的治疗 治疗前后的人类活检和小鼠模型。目标1假设检查点抑制 诱导涉及免疫肿瘤和免疫免疫串扰的复杂和顺序的网络响应。 这是AIM 1具有执行PDO的串行时间顺序采样的能力来定义单个细胞RNA-Seq 早期抗PD-1刺激的抗肿瘤免疫激素的网络蜂窝串扰模型超过多个 几个月后进行的临床活检通常无法访问急性时间点。重要的是,比较 反应与非反应小鼠和人类器官的这种免疫磷脂将定义淋巴结 积分会议抵抗。 AIM 2通过使用PDO作为生活 通过抗PD-1检查点抑制来富含肿瘤反应性小鼠和人黑色素瘤的生物反应器, 然后在体外和体内测试增强的抗肿瘤活性。最后,AIM 3执行共同处理 试验比较了治疗活检CSCC PDOS与临床结果的抗PD-1反应。此外, 用抗PD-1重新挑战治疗活检PDO,并通过新颖的药物使PD-1灭活PD-1 去磷酸化。因此,我们利用保留内源性肿瘤上皮和免疫的整体PDO模型 组成部分通过我们的Calvin Kuo团队(Organoids),调查和改善癌症免疫疗法, 马克·戴维斯(Mark Davis)和克里斯·加西亚(Chris Garcia)(肿瘤免疫学)以及安妮·张(Anne Chang)和迪米特里·科尔瓦斯(Dimitri Colevas)(CSCC临床医生)。

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

CALVIN J KUO的其他基金

Intestinal organoid modeling of SARS-CoV-2-stimulated innate and adaptive immunity
SARS-CoV-2 刺激的先天性和适应性免疫的肠道类器官模型
  • 批准号:
    10319858
    10319858
  • 财政年份:
    2021
  • 资助金额:
    $ 64.36万
    $ 64.36万
  • 项目类别:
TOOLKIT Core
工具包核心
  • 批准号:
    10272362
    10272362
  • 财政年份:
    2021
  • 资助金额:
    $ 64.36万
    $ 64.36万
  • 项目类别:
Core 2: Stanford Breast Metastasis Center Organoid Core
核心 2:斯坦福乳腺转移中心类器官核心
  • 批准号:
    10704695
    10704695
  • 财政年份:
    2021
  • 资助金额:
    $ 64.36万
    $ 64.36万
  • 项目类别:
Core 2: Stanford Breast Metastasis Center Organoid Core
核心 2:斯坦福乳腺转移中心类器官核心
  • 批准号:
    10272393
    10272393
  • 财政年份:
    2021
  • 资助金额:
    $ 64.36万
    $ 64.36万
  • 项目类别:
Immunotherapy Modeling in Organoids Co-preserving Tumor and Infiltrating Immune Compartments
共保存肿瘤和浸润免疫区室的类器官的免疫治疗模型
  • 批准号:
    10212018
    10212018
  • 财政年份:
    2021
  • 资助金额:
    $ 64.36万
    $ 64.36万
  • 项目类别:
TOOLKIT Core
工具包核心
  • 批准号:
    10706501
    10706501
  • 财政年份:
    2021
  • 资助金额:
    $ 64.36万
    $ 64.36万
  • 项目类别:
Intestinal organoid modeling of SARS-CoV-2-stimulated innate and adaptive immunity
SARS-CoV-2 刺激的先天性和适应性免疫的肠道类器官模型
  • 批准号:
    10654752
    10654752
  • 财政年份:
    2021
  • 资助金额:
    $ 64.36万
    $ 64.36万
  • 项目类别:
Immunotherapy Modeling in Organoids Co-preserving Tumor and Infiltrating Immune Compartments
共保存肿瘤和浸润免疫区室的类器官的免疫治疗模型
  • 批准号:
    10586140
    10586140
  • 财政年份:
    2021
  • 资助金额:
    $ 64.36万
    $ 64.36万
  • 项目类别:
Intestinal organoid modeling of SARS-CoV-2-stimulated innate and adaptive immunity
SARS-CoV-2 刺激的先天性和适应性免疫的肠道类器官模型
  • 批准号:
    10450851
    10450851
  • 财政年份:
    2021
  • 资助金额:
    $ 64.36万
    $ 64.36万
  • 项目类别:
Organoid Core B
类器官核心B
  • 批准号:
    10178731
    10178731
  • 财政年份:
    2020
  • 资助金额:
    $ 64.36万
    $ 64.36万
  • 项目类别:

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