Autohistomagnetic Isolation of Tumor-reactive T-cells

肿瘤反应性 T 细胞的自组织磁分离

• 批准号: 9884541
• 负责人: Adam William Mailloux
• 金额: $ 10.96万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2020-11-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884541
• 关键词: Adoptive Cell Transfers; Adoptive Transfer; Allogenic; Antibodies; Antigen Presentation; Antitumor Response; Autoimmune Diseases; Autologous; Autologous Tumor-Infiltrating Lymphocyte; Back; Basic Science; Binding; Biopsy; CD3 Antigens; Cell Line; Cells; Cervix carcinoma; Clinical; Clinical Trials; Clone Cells; Complex; Consumption; Disease; Dose; Effectiveness; Eligibility Determination; Epitopes; Evaluation; Excision; Fostering; Frequencies; Future; Government; Hour; Human; Immune response; Immunooncology; Immunotherapy; Incubated; Infusion procedures; Interferon Type II; Interleukin-2; Kinetics; Leukocytes; Life; Magnetism; Major Histocompatibility Complex; Malignant Neoplasms; Mechanics; Mediating; Metastatic Melanoma; Methodology; Methods; Molecular Conformation; Mus; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Patients; Peptides; Persons; Phenotype; Process; Property; Protocols documentation; Resected; Sampling; Savings; Specificity; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Translating; Tumor Antigens; Tumor Expansion; Tumor-Derived; Tumor-Infiltrating Lymphocytes; Work; autoreactive T cell; base; beta-2 Microglobulin; cancer regression; cancer therapy; cost; exhaustion; experimental study; fighting; immunogenic; immunogenicity; improved; lymphocyte product; magnetic beads; mouse model; neoantigens; neoplastic cell; new technology; pre-clinical; prospective; prototype; response; screening; success; treatment response; tumor; tumor infiltrating lymphocyte therapy

Adoptive cell therapy of autologous tumor-infiltrating lymphocytes (TIL) can now mediate objective cancer regression in 50% of patients with metastatic melanoma. While TIL therapy has made incremental improvements over recent decades, the fundamental methodologies have not significantly changed despite major advances in the field of immuno-oncology. Current protocols for TIL therapy focus on the ex vivo expansion of TIL from resected tumor biopsies using high-dose interleukin-2 over many weeks. This is a time- consuming and expensive process that limits the eligibility of many patients and reduces the number of cancer treatment facilities capable of offering this life-saving therapy. The most important factors governing clinical response are the anti-tumor reactivity of the final TIL infusion product, and the total number of TIL generated for adoptive transfer. Current methodologies are torn between the need to expand TIL quickly to maintain a “young” phenotype that avoids exhaustion and the induction of tolerance, and the need to enrich for tumor- reactive TIL. We propose a novel technology called autohistomagnetic isolation (AHMI) that uses patient tumor-derived antigen presentation complex to select for reactive TIL within the first 48 hours after biopsy. The basic principle of this new methodology uses conformation-dependent antibodies to immunoprecipitate heterotrimers of HLA or H2-Kb, β-2 microglobulin, and cognate peptide onto magnetic beads. The resulting construct can then isolate tumor-reactive TIL from non-reactive TIL using any magnetic separation platform among positively selected bulk TIL cultures. This will greatly reduce the time needed to generate TIL infusion products, will result in a more potent and persistent TIL phenotype, reduce cost, and increase anti-tumor reactivity. We propose to fully optimize AHMI and interrogate the subsequent TIL infusion product in a pre- clinical murine model of TIL therapy, and in samples from patients with metastatic melanoma. The completion of the studies proposed here will produce a fully functional prototype for mouse and human AHMI and lay the groundwork necessary for clinical trials.

自体肿瘤浸润淋巴细胞（TIL）的过继细胞疗法现在可以介导客观癌症 50% 的转移性黑色素瘤患者的病情得到缓解，而 TIL 治疗则取得了进展。 尽管近几十年来有所改进，但基本方法并没有发生重大变化 免疫肿瘤学领域的重大进展目前的 TIL 治疗方案主要集中在体外。 使用高剂量白细胞介素 2 在数周内从切除的肿瘤活检中扩增 TIL。 耗时且昂贵的过程限制了许多患者的资格并减少了癌症的数量 能够提供这种挽救生命的治疗的治疗设施是控制临床的最重要因素。 反应是最终 TIL 输注产品的抗肿瘤反应性，以及生成的 TIL 总数 目前的方法在快速扩展 TIL 和维持 TIL 之间存在矛盾。 “年轻”的表型可以避免疲劳和诱导耐受性，以及富集肿瘤的需要 我们提出了一种称为自组织磁隔离 (AHMI) 的新技术，该技术使用患者。 肿瘤源性抗原呈递复合物，用于在活检后 48 小时内选择反应性 TIL。 这种新方法的基本原理是使用构象依赖性抗体进行免疫沉淀 HLA 或 H2-Kb、β-2 微球蛋白和同源肽的异三聚体到磁珠上。 然后，构建体可以使用任何磁性分离平台将肿瘤反应性 TIL 与非反应性 TIL 分离 在积极选择的大量 TIL 培养物中，这将大大减少产生 TIL 输注所需的时间。 产品，将产生更有效和持久的 TIL 表型，降低成本并增强抗肿瘤效果 我们建议全面优化 AHMI 并在预测试中询问后续的 TIL 输注产品。 TIL 疗法的临床小鼠模型，并在转移性黑色素瘤患者的样本中完成。 这里提出的研究将为小鼠和人类 AHMI 产生一个功能齐全的原型，并奠定 临床试验所需的基础。