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Programming Metabolically Fit TILs for Immunotherapy

为免疫疗法编程适合代谢的 TIL

基本信息

批准号：
10822377
负责人：
Shikhar Mehrotra
金额：
$ 100万
依托单位：
LIPO-IMMUNO TECH, LLC
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：
2020-02-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10822377
关键词：
Adopted Adoptive Cell Transfers Adoptive Transfer Affinity Antigens Appearance B lymphoid malignancy CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Cell Death Cell Death Induction Cells Cellular Metabolic Process Chronic Clinical Cytotoxic T-Lymphocytes Data Dependence Dose Engineering Engraftment Epitopes Exhibits FOXP3 gene Future Generations Genetic Engineering Glutamine Goals Helper-Inducer T-Lymphocyte Human Hybrids IL17 gene IL2 gene Immunosuppression Immunotherapy Infiltration Infusion procedures Interferon Type II Interleukin-15 Investigational Drugs Investigational New Drug Application Lead Logistics Lytic Malignant Neoplasms Malignant neoplasm of prostate Memory Metabolic Metabolic stress Metastatic breast cancer Methodology Methods Mitochondria Molecular Biology Mutate Nutrient PPBP gene Pathway interactions Patients Phase Phase I Clinical Trials Phase I/II Clinical Trial Phenotype Predisposition Primary Neoplasm Prostatic Neoplasms Protocols documentation Publications Publishing Regulatory T-Lymphocyte Reporting Research Resources Solid Neoplasm T cell therapy T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets TC1 Cell TNF gene Testing Th1 Cells Time Tumor Antigens Tumor Escape Tumor Expansion Tumor Suppression Tumor-Infiltrating Lymphocytes United States Food and Drug Administration Variant Viral Woman chimeric antigen receptor commercialization cost cytokine cytotoxic cytotoxic CD8 T cells design effector T cell efficacy testing engineered T cells exhaustion feasibility testing immunogenic immunotherapy clinical trials improved in vivo in vivo Model interleukin-21 melanoma metabolic phenotype neoantigens neoplastic cell novel patient derived xenograft model phase 1 study preclinical study programs response senescence stem-like cell stemness transdifferentiation tumor tumor growth tumor microenvironment tumor xenograft

项目摘要

ABSTRACT Advances in molecular biology and genetic engineering have led to the design and use of modified T cells recognize tumors to achieve significant tumor control upon adoptive cell transfer (ACT) to patients. These T cells are either transduced with tumor antigen reactive T cell receptors (TCR), or chimeric antigen receptors (CARs). Recently, a surge in studies with neo-antigen reactive T cells or T cells recognizing novel mutated antigens has also shown promise. While the implementation of these studies requires significant technical resources, the appearance of antigen loss variants also leads to less effective tumor control when using effector T cells reactive to single tumor antigen or target molecule. Thus, there is a resurgence in using tumor infiltrating lymphocytes (TILs), which have endogenous T cells reactive to multiple tumor epitopes, for ACT. While most studies have used the conventional approach to expand TILs using high dose IL2, some recent studies using IL15 or IL21 showed improved tumor control. Preclinical studies have also shown that different subsets of both helper CD4+ T helper (Th) cells and CD8+ T cytotoxic (Tc) cells hold promise for clinical use in ACT protocols. Importantly, T helper cell subsets with the ability to secrete IL-17 (Th17) have been shown to possess stem cell like phenotype that attributes to their long-term persistence and leads to improved tumor control tumors as compared to the Th1 subsets (that secrete IFNγ, IL2, TNFα). However, contrary to these observations there are reports that Tc1 cells exhibit improved tumor control as compared to Tc17 cells. These differences in T cell subsets response to control tumors, is compounded by the fact that in the suppressive tumor microenvironment a large fraction of these Th or Tc subsets acquire FoxP3+ regulatory phenotype, become dysfunctional or undergo cell death leading to tumor reversion. Thus, ex vivo programming conditions that can render a stable phenotype with reduced ‘plasticity’ and not only controls primary tumors, but also results in formation of anti-tumor memory will be of immense importance in ACT. We have recently established that programming conditions that bring together ‘anti-tumor effector function’ of Th1 cells and ‘stemness’ of Th17 cells lead to a superior hybrid Th1/17 (and Tc/17) cell exhibiting long-term tumor control. Thus, in the Phase I application we successfully tested the feasibility of programming metabolically enhanced signature to TILs from melanoma and prostate cancer patients. For the Phase II application, we hypothesize that ex vivo programming and expansion using hybrid T1/17 (Th1/17 and Tc1/17) culture conditions will result in a robust anti-tumor control even with fewer adoptively transferred clinical grade metabolically enhanced TILs (meTILs). Following specific aims are proposed to establish and develop our approach for commercialization: Specific Aim 1: To generate clinical-grade hybrid meTILs from melanoma and prostate cancer patients. Specific Aim 2: To establish if clinical grade hybrid meTILs are superior to conventional TILs in controlling tumor growth in vivo. We believe that this proposal will help adopt the novel ex vivo programming conditions for generating hybrid meTILs that could be used future in adoptive T- cell immunotherapy clinical trials.

摘要