权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

抽象的分子生物学和基因工程的进步导致了修饰 T 细胞的设计和使用识别肿瘤，以在过继细胞移植（ACT）给患者后实现显着的肿瘤控制。这些T细胞是用肿瘤抗原反应性 T 细胞受体 (TCR) 或嵌合抗原受体 (CAR) 转导的。最近，关于新抗原反应性 T 细胞或识别新突变抗原的 T 细胞的研究激增也表现出了希望。虽然这些研究的实施需要大量的技术资源，当使用反应性T细胞时，抗原丢失变异的出现也会导致肿瘤控制效果较差单一肿瘤抗原或靶分子。因此，使用肿瘤浸润淋巴细胞的趋势再次出现 (TIL)，其具有对多个肿瘤表位有反应的内源性 T 细胞，用于 ACT。虽然大多数研究都使用传统方法使用高剂量 IL2 来扩展 TIL，最近的一些研究使用 IL15 或 IL21 显示出改善的肿瘤控制。临床前研究还表明，辅助 CD4+ 的不同子集 T 辅助 (Th) 细胞和 CD8+ T 细胞毒性 (Tc) 细胞有望在 ACT 方案中用于临床。重要的是，T 具有分泌 IL-17 (Th17) 能力的辅助细胞亚群已被证明具有干细胞样表型与 Th1 相比，这归因于它们的长期持续性并导致肿瘤控制得到改善子集（分泌 IFNγ、IL2、TNFα）。然而，与这些观察相反，有报道称 Tc1 细胞与 Tc17 细胞相比，表现出更好的肿瘤控制。 T 细胞亚群对对照反应的这些差异肿瘤，由于以下事实而变得更加复杂：在抑制性肿瘤微环境中，这些 Th 的很大一部分或 Tc 亚群获得 FoxP3+ 调节表型，变得功能失调或经历细胞死亡，导致肿瘤逆转。因此，离体编程条件可以提供稳定的表型，并减少 “可塑性”不仅能控制原发肿瘤，还能导致抗肿瘤记忆的形成在 ACT 中非常重要。我们最近建立了将 Th1 细胞的“抗肿瘤效应功能”和 Th17 细胞的“干性”导致了优异的杂交 Th1/17（以及 Tc/17) 细胞表现出长期肿瘤控制。因此，在第一阶段的应用中我们成功地测试了对黑色素瘤和前列腺癌 TIL 进行代谢增强特征编程的可行性患者。对于 II 期应用，我们假设使用混合的离体编程和扩展 T1/17（Th1/17 和 Tc1/17）培养条件即使采用较少的收养也将产生强大的抗肿瘤控制转移临床级代谢增强 TIL (meTIL)。提出以下具体目标建立和开发我们的商业化方法：具体目标 1：产生临床级混合动力来自黑色素瘤和前列腺癌患者的 meTIL。具体目标 2：确定临床级混合 meTIL 是否有效在控制体内肿瘤生长方面优于传统的 TIL。我们相信该提案将有助于采纳用于生成混合 meTIL 的新型离体编程条件，可用于未来的过继性 T- 细胞免疫治疗临床试验。