Determining mechanisms of enhanced antitumor efficacy of four-day expanded Th17 cells for adoptive transfer

确定用于过继转移的四天扩增 Th17 细胞增强抗肿瘤功效的机制

• 批准号: 10462684
• 负责人: Hannah Marie Knochelmann
• 金额: $ 3.7万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462684
• 关键词: Address; Adoptive Cell Transfers; Adoptive Transfer; Animals; Antibodies; Antitumor Response; CCL2 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CSF3 gene; Cell Therapy; Cells; Chemotactic Factors; Clinical; Clinical Protocols; Consumption; Cytokine Receptors; Cytometry; Dose; Engraftment; Equilibrium; Exposure to; FDA approved; Future; Immune; Immune response; Immunity; Infusion procedures; Interleukin-17; Interleukin-6; Investigation; Kinetics; Lymphocyte; Lymphoid Cell; Malignant Neoplasms; Mediating; Memory; Metastatic Melanoma; Methods; Modeling; Mus; Myeloid Cells; Natural Killer Cells; Pathway interactions; Patients; Peripheral; Process; Production; Protocols documentation; Recurrence; Regulatory T-Lymphocyte; Reporting; Role; Shapes; Solid Neoplasm; Supplementation; T cell therapy; T-Lymphocyte; Testing; Time; Toxic effect; Translating; Treatment outcome; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Work; base; comparative efficacy; cost; cytokine; improved; in vivo; lymphocyte product; macrophage; melanoma; monocyte; neutrophil; novel; novel strategies; preclinical study; prevent; recruit; response; tumor; unpublished works

ABSTRACT Adoptive T cell transfer therapy mediates potent immunity in patients with bulky metastatic malignancies, but proves difficult to translate clinically due to production costs, time, and labor required to generate T cell infusion products. To overcome such obstacles, we proposed a method of shortened ex vivo expansion using Th17 cells to treat melanoma. Our new unpublished work indicates that Th17 cells expanded only four days ex vivo can eradicate tumors even when only very few cells (~200K) are infused into the animal. These day-4 Th17 cells mediate more potent antitumor responses than greater numbers (>25X more) of Th17 cells expanded long term. In contrast to long-term expanded cells, day-4 cells 1) persist at greater fold once infused in the animal, 2) induce significantly increased production of multiple cytokines (IL-6, G-CSF, MCP-1, KC), 3) express high levels of cytokine receptors and costimulatory molecules, and 4) provide long-lived protection against tumor recurrence. This proposal will determine the mechanism of enhanced day-4 Th17 cell antitumor efficacy and examine whether 4-days of ex vivo expansion will improve clinical protocols for generating tumor-infiltrating lymphocyte (TIL) products with superior efficacy. Based on our findings, we propose the central hypothesis that day-4 expanded Th17 cells possess enhanced efficacy in vivo due to their unique ability to recruit other immune cells to the tumor as well as form durable memory. To test this hypothesis, in Aim 1, we will examine the effects of IL- 6 on shaping memory and antitumor activity of Th17 cells via neutralization versus exogenous supplementation of IL-6. In Aim 2, we will determine whether the antitumor efficacy of very few day-4 Th17 cells is reliant upon host immunity through antibody depletion of host neutrophils, macrophages, NK cells, and lymphocytes. Finally, in Aim 3, we will assess the functionality of TIL products kinetically during ex vivo expansion and determine whether 4-days of rapid expansion is superior to clinically standard 14-days. These investigations are expected to expose key mechanisms underlying short-term expanded Th17 cell potency to 1) identify novel approaches to improve ACT with long-term expanded cells and 2) highlight shortened expansion as an efficient, less expensive method for future ACT (recently FDA approved at a cost of >$500,000/infusion).

摘要 连续性T细胞转移治疗介导了巨大转移性恶性肿瘤患者的有效免疫， 由于产生T细胞输注所需的生产成本、时间和劳动力， 产品.为了克服这些障碍，我们提出了一种使用Th 17细胞缩短体外扩增的方法 来治疗黑素瘤我们新的未发表的工作表明，体外扩增仅4天的Th 17细胞可以 即使只有很少的细胞（~ 200 K）注入动物体内，也能根除肿瘤。这些第4天的Th 17细胞 介导比长期扩增的更多数量（> 25倍多）的Th 17细胞更有效的抗肿瘤应答。 与长期扩增的细胞相比，第4天的细胞1）一旦输注到动物中就以更大的倍数持续存在，2）诱导 显著增加多种细胞因子（IL-6、G-CSF、MCP-1、KC）的产生，3）表达高水平的 细胞因子受体和共刺激分子，和4）提供针对肿瘤复发的长期保护。 该提议将确定增强的第4天Th 17细胞抗肿瘤功效的机制，并检查 4天的离体扩增是否会改善产生肿瘤浸润淋巴细胞的临床方案 (TIL)具有上级功效的产品。基于我们的发现，我们提出了中心假设，即第4天 扩增的Th 17细胞由于其募集其它免疫细胞的独特能力而具有增强的体内功效 并形成持久记忆。为了验证这一假设，在目标1中，我们将检查IL-10对小鼠的影响。 6对Th 17细胞通过中和与外源性补充的形状记忆和抗肿瘤活性的影响 IL-6在目标2中，我们将确定非常少的第4天Th 17细胞的抗肿瘤功效是否依赖于 通过宿主嗜中性粒细胞、巨噬细胞、NK细胞和淋巴细胞的抗体耗竭实现宿主免疫。最后， 在目标3中，我们将在离体扩增过程中动力学地评估TIL产物的功能，并确定 4天快速扩增是否上级临床标准14天。这些调查 预期将揭示短期扩增的Th 17细胞效力的关键机制，以1）鉴定 用长期扩增的细胞改善ACT的新方法和2）突出缩短的扩增 作为未来ACT的一种有效，更便宜的方法（最近FDA批准， >$500，000/输注）。

项目成果

Programmed death 1 (PD-1) and ligand (PD-L1) inhibitors in head and neck squamous cell carcinoma: A meta-analysis.

• DOI: 10.1002/wjo2.15
• 发表时间: 2022-09
• 期刊: World journal of otorhinolaryngology - head and neck surgery