Programming Metabolically Fit TILs for Immunotherapy

为免疫疗法编程适合代谢的 TIL

• 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
• 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

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.

摘要 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 在过继细胞转移(ACT)给患者时，识别肿瘤以实现显著的肿瘤控制。这些T 细胞通过肿瘤抗原反应性T细胞受体(TCR)或嵌合抗原受体进行转导 (汽车)。最近，利用新抗原反应性T细胞或识别新突变的T细胞的研究激增 抗原也显示出了希望。虽然这些研究的实施需要大量的技术支持 资源，抗原丢失变体的出现也会导致在使用 效应性T细胞与单个肿瘤抗原或靶分子发生反应。因此，使用TIL的现象卷土重来， 对于ACT，具有与多种肿瘤表位反应的内源性T细胞。虽然大多数研究都使用了 使用高剂量IL2扩展TIL的传统方法，最近使用IL15或IL21的一些研究表明 改善了肿瘤控制。临床前研究还表明，这两种辅助细胞亚群的不同 (TH)细胞和CD8+T细胞毒性(TC)细胞有望在ACT方案中得到临床应用。重要的是，T助手 具有分泌IL-17(Th17)能力的细胞亚群已被证明具有干细胞样表型， 归因于它们的长期持久性，并导致与Th1相比，肿瘤控制得到改善 亚群(分泌干扰素γ、白介素2、肿瘤坏死因子α)。然而，与这些观察相反的是，有报道称Tc1 与Tc17细胞相比，细胞表现出更好的肿瘤控制能力。T细胞亚群反应的这些差异 控制肿瘤，是因为在抑制性肿瘤微环境中，很大一部分 这些Th或Tc亚群获得FoxP3+调节表型，变得功能障碍或经历细胞死亡 导致肿瘤逆转。因此，体外编程条件可以呈现稳定的表型与 可塑性降低，不仅控制了原发肿瘤，还导致了抗肿瘤记忆意志的形成 在行动中具有极其重要的意义。我们最近确定，编程条件会带来 Th1细胞的“抗肿瘤效应功能”和Th17细胞的“干细胞性”共同导致了优良的Th1/17杂交体。 (和TC/17)细胞表现出长期的肿瘤控制。因此，我们假设体外扩增和 将TIL编程为杂交T1/17(Th1/17和Tc1/17)表型将导致甚至强大的抗肿瘤控制 采用较少的过继转移细胞。提出以下具体目标，以建立和发展我们的 商业化途径：具体目标1：确定人黑色素瘤来源的TIL是否可以 体外编程强大的抗肿瘤杂交种T1/17表型。具体目标2：确定混合TILs 在体内控制黑色素瘤生长方面优于传统的TIL。我们认为，这项提议 将有助于采用新颖的体外编程条件来生成强大的抗肿瘤TIL，这种TIL可能 未来用于过继T细胞免疫治疗的临床试验。