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Genetically engineering T cells to overcome the immunosuppressive melanoma microenvironment

基因工程 T 细胞克服免疫抑制性黑色素瘤微环境

基本信息

批准号：
10224671
负责人：
Samantha Marie Fix
金额：
$ 1.6万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2021-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224671
关键词：
Adoptive Cell Transfers Adoptive Transfer Autoimmune Diseases Automobile Driving Binding Bioinformatics CD8-Positive T-Lymphocytes Cell Therapy Cell surface Cells Cellular Metabolic Process Clinic Clustered Regularly Interspaced Short Palindromic Repeats Complex Cytotoxic T-Lymphocytes Dendritic Cells Down-Regulation Engineering Environment Flow Cytometry Functional disorder Genes Genetic Engineering Goals Human ITIM Image Immune Immunosuppression Immunotherapy Impairment Interleukin-10 Knock-out Ligands Mediating Metastatic Melanoma Methods Modeling Mus Pathway interactions Patients Phenotype Positioning Attribute Production Research Resistance Ribonucleoproteins Risk Sampling Signal Transduction Solid Neoplasm Spatial Distribution Surface T cell therapy T-Cell Activation T-Lymphocyte Therapeutic Translations Tumor Escape Tumor-Derived Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Work anti-PD-L1 cancer immunotherapy cell type checkpoint receptors checkpoint therapy cytokine engineered T cells exhaustion experience experimental study fitness immune checkpoint blockade immune-related adverse events improved improved functioning knockout gene melanoma metabolic fitness mouse model neoplastic cell novel novel strategies patient subsets programs receptor response translational impact treatment strategy tumor tumor microenvironment tumor-immune system interactions

项目摘要

ABSTRACT While checkpoint immunotherapy has transformed the treatment of metastatic melanoma over the past decade, this therapy fails to provide durable responses for the majority of patients. Immunotherapy resistance in solid tumors is often driven by the immunosuppressive tumor microenvironment (TME), which dampens the anti-tumor capacity of incoming T cells. In this proposal, I aim to genetically engineer T cells to overcome a key pathway of immunosuppression which I identified using an unbiased bioinformatics screen. I aim to improve the function of adoptively transferred T cells by using CRISPR to knockout the expression of this key immune inhibitory receptor expressed on the T cell surface. I have already developed a method to knockout this gene efficiently in murine and human T cells, and through this proposal, I will determine the effect of gene knockout on intrinsic T cell fitness and function (Aim 1), T cell accumulation and function in the melanoma microenvironment (Aim 2), and T cell anti-tumor efficacy (Aim 3). I expect that this research will yield a translational method to improve the function of adoptively transferred T cells in the immunosuppressive melanoma TME. Our team has demonstrated the ability to take novel T cell therapies from the lab to the clinic, and our established program to treat patients with genetically-engineered T cells will ease translation.

摘要