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：
9906726
负责人：
Shikhar Mehrotra
金额：
$ 22.46万
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 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906726
关键词：
Adopted Adoptive Cell Transfers Adoptive Transfer Affinity Antigens Appearance CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cancer Patient Cell Death Cells Cellular Metabolic Process Chronic Clinical Dependence Dose Engineering Engraftment Epitopes Exhibits FOXP3 gene Future Generations Genetic Engineering Glutamine Helper-Inducer T-Lymphocyte Human Hybrids IL2 gene Immunosuppression Immunotherapy Infusion procedures Interferon Type II Interleukin-15 Interleukin-17 Lead Logistics Lytic Malignant Neoplasms Memory Metabolic Metabolic stress Metastatic breast cancer Methodology Methods Mitochondria Molecular Biology Molecular Genetics Mutate Natural Killer Cells Nutrient PPBP gene Pathway interactions Patients Phase I Clinical Trials Phenotype Predisposition Primary Neoplasm Protocols documentation Publications Publishing Regulatory T-Lymphocyte Reporting Research Resources Solid Neoplasm Standardization T cell therapy T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets TC1 Cell TNF gene Testing Th1 Cells Time Tumor Antigens Tumor Suppression Tumor-Derived Tumor-Infiltrating Lymphocytes Variant Viral Woman Xenograft Model chimeric antigen receptor commercialization cost cytokine cytotoxic design effector T cell engineered T cells exhaustion experimental study immunotherapy clinical trials improved in vivo in vivo Model interleukin-21 melanoma neoantigens neoplastic cell novel preclinical study programs response senescence stem-like cell stemness tumor tumor growth tumor microenvironment

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 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) cells exhibiting long-term tumor control. Thus, we hypothesize that ex vivo expansion and programming of TILs to hybrid T1/17 (Th1/17 and Tc1/17) phenotype will lead to robust anti-tumor control even with fewer adoptively transferred cells. Following specific aims are proposed to establish and develop our approach for commercialization: Specific Aim 1: To determine if human melanoma tumor derived TILs could be ex vivo programmed to potent anti-tumor hybrid T1/17 phenotype. Specific Aim 2: To establish if hybrid TILs are superior to conventional TILs in controlling melanoma tumor growth in vivo. We believe that this proposal will help adopt the novel ex vivo programming conditions for generating robust anti-tumor TILs that could be used future in adoptive T-cell immunotherapy clinical trials.

抽象的分子生物学和基因工程的进步导致了修饰的T细胞的设计和使用识别肿瘤在收养细胞转移（ACT）中获得明显的肿瘤控制细胞用肿瘤抗原反应性T细胞受体（TCR）或嵌合抗原受体转导（CARS）。抗原也表现出希望。资源，抗原损失变体的外观也导致肿瘤控制较少效应T细胞对单个肿瘤抗原或靶标分子有反应。虽然内源性T细胞对多个肿瘤表位反应，但大多数研究都使用了您。使用高剂量IL2扩展TIL的常规方法，一些使用IL15或IL21的研究表明改善的肿瘤控制还表明（Th）细胞和CD8+ T细胞毒性（TC）细胞在ACT方案中有望进行临床使用具有分泌IL-17（Th17）能力的细胞子集是具有像表型的干细胞一样与th1相比，其Lomors肿瘤的归因于Th1 Th1 Th1 亚群（分泌IFNγ，IL2，TNFα）。与TC17细胞相比，细胞表现出改善的肿瘤控制。控制肿瘤是由抑制性肿瘤微涉及大部分的事实所构成的这些TC子集获取FOXP3+调节表型，变得功能失调或患有细胞死亡因此，导致肿瘤恢复。减少了“塑料”，而不是不可能导致形成反肿瘤记忆记忆记忆的结果。威尔·威尔！在法案中非常重要。 Th1细胞的“抗肿瘤有效功能”和Th17细胞的“茎”导致了杂种TH1/17/17 （和TC/17）表现出长期肿瘤的细胞。将TILS编程到混合T1/17（TH1/17和TC1/17）表型甚至都会导致强大的抗肿瘤控制提出了较少的经过转移的细胞。商业化方法：特定目的1：确定人黑色素瘤肿瘤是否可能是实体编程为有效的抗肿瘤杂交T1/17表型。在体内控制黑色素瘤肿瘤生长方面优于常规til。将有助于采用新颖的离体编程条件，以产生强大的抗肿瘤tils tils 在收养T细胞免疫疗法临床中使用了未来。