Programming Metabolically Fit TILs for Immunotherapy

为免疫疗法编程适合代谢的 TIL

• 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
• 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

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 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(CARS)进行转导。 最近，对新抗原反应性T细胞或识别新突变抗原的T细胞的研究激增 也显示出了希望。虽然实施这些研究需要大量的技术资源，但 当使用效应性T细胞反应时，抗原丢失变异体的出现也会导致肿瘤控制效果降低 结合单个肿瘤抗原或靶分子。因此，使用肿瘤浸润性淋巴细胞的做法又重新流行起来。 (TIL)，具有与多种肿瘤表位反应的内源性T细胞，用于ACT。虽然大多数研究都有 使用常规方法使用高剂量IL2来扩展TIL，最近的一些研究使用IL15或IL21 显示出肿瘤控制的改善。临床前研究也表明，这两种辅助细胞亚群的不同 辅助性T细胞(Th)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 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 这归因于它们的长期持久性，并导致与Th1相比，肿瘤控制得到了改善 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细胞 与Tc17细胞相比，显示出更好的肿瘤控制。T细胞亚群对对照反应的这些差异 肿瘤，是因为在抑制性肿瘤微环境中，很大一部分Th 或者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，能够使稳定的表型减少的体外编程条件 ‘可塑性’，不仅控制了原发肿瘤，还导致了抗肿瘤记忆的形成 在ACT中具有极其重要的意义。我们最近确定，将编程条件集中在一起 Th1细胞的“抗肿瘤效应功能”和Th17细胞的“干细胞性”导致了优秀的Th1/17杂交细胞(和 TC/17)细胞表现出长期的肿瘤控制。因此，在第一阶段应用程序中，我们成功地测试了 对黑色素瘤和前列腺癌的TIL编程代谢增强信号的可行性 病人。对于第二阶段的应用，我们假设体外编程和扩展使用混合 T1/17(Th1/17和Tc1/17)培养条件将导致强大的抗肿瘤控制，即使采用较少的 转移性临床分级代谢增强型TIL(MeTILs)。提出了以下具体目标 建立和发展我们的商业化方法：具体目标1：生产临床级混合动力车 黑色素瘤和前列腺癌患者的meTIL。具体目标2：建立临床级别的混合meTIL 在控制体内肿瘤生长方面优于传统的TIL。我们相信，这项建议将有助于通过 新的体外编程条件产生的杂交mTIL，可用于未来采用T- 细胞免疫治疗临床试验。