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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：
10212018
负责人：
CALVIN J KUO
金额：
$ 65.79万
依托单位：
STANFORD UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/10212018
关键词：
3-Dimensional Acute Address Adoptive Cell Transfers Adoptive Transfer Aftercare Air Antigens Autologous B-Lymphocytes Biopsy Bioreactors Cells Cellular immunotherapy Clinical Coculture Techniques Complex Cutaneous Data Detection Development Epithelial Equilibrium Exhibits Human Immune Immune Evasion Immune checkpoint inhibitor Immune response Immune system Immunologic Surveillance Immunological Models Immunotherapeutic agent Immunotherapy In Vitro Interleukin-2 Invaded Ligands Liquid substance MHC antigen Malignant Neoplasms Methods Modeling Mus Natural Killer Cells Nature Nodal Organoids Outcome Patients Peptides Phosphoric Monoester Hydrolases Population Primary Neoplasm Progressive Disease Protein Dephosphorylation Receptor Inhibition Resistance Resolution Sampling System T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets T-cell receptor repertoire TNFRSF5 gene Techniques Testing Therapeutic Therapeutic antibodies Time Transgenic Mice Tumor Antigens Tumor Cell Line Tumor-Derived Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells air treatment anti-PD-1 anti-PD-1/PD-L1 anti-PD-L1 anti-PD1 therapy anti-tumor immune response base cancer immunotherapy cell killing checkpoint inhibition clinical decision-making clinical efficacy cohesion cohort cytotoxicity exhaust follow-up human model immune checkpoint blockade improved in vitro Model in vitro activity in vivo macrophage melanoma mouse model neoplastic cell network models next generation novel patient response patient subsets peripheral blood predictive marker preservation programmed cell death ligand 1 programmed cell death protein 1 prospective receptor reconstitution recruit response restraint single-cell RNA sequencing skin squamous cell carcinoma success treatment trial trial comparing tumor tumor immunology tumor progression tumor specificity tumorigenesis

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).

项目总结