VLA-4–targeted 67Cu-LLP2A preconditioning enhances efficacy of T-cell-based adoptive immunotherapy

VLA-4™ 靶向 67Cu-LLP2A 预处理增强基于 T 细胞的过继免疫疗法的疗效

基本信息

批准号：
10713034
负责人：
Ravi Bhasker Patel
金额：
$ 59.58万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-05 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10713034
关键词：
A/J Mouse Adoptive Cell Transfers Adoptive Immunotherapy Adult Affinity Behavior Therapy Binding Biodistribution CRISPR/Cas technology Cell Death Induction Cell Lineage Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Cellular immunotherapy Childhood Cyclophosphamide Disease remission Dose Engraftment Ensure Failure Future Image Immune Immunotherapy In Vitro Infusion procedures Integrin alpha4beta1 Label Lymphocyte Malignant Neoplasms Measures Mediating Modeling Mus Myelogenous Neural Crest Cell Neuroblastoma Organ Patient-Focused Outcomes Patients Penetration Phenotype Proliferating Radiation Radionuclide therapy Refractory Regimen Site Solid Neoplasm T cell therapy T-Lymphocyte Testing Tissues Toxic effect Translations Tumor Burden Validation Whole-Body Irradiation X-Ray Computed Tomography cell killing chemotherapy chimeric antigen receptor chimeric antigen receptor T cells conditioning cost cytotoxic dosimetry early phase clinical trial fludarabine immune clearance improved improved outcome in vivo leukemia melanoma neoplastic cell novel peptidomimetics pre-clinical preclinical study preconditioning radiation risk risk mitigation single photon emission computed tomography small molecule success transcriptome tumor tumor microenvironment

项目摘要

Project Summary & Abstract Adoptive T cell therapies (ACT) including chimeric antigen receptor (CAR) T cells are novel immunotherapies with unparalleled successes, especially in patients with leukemia. However, they have limited efficacy in solid tumors. One barrier to success is the ability of ACT to penetrate the solid tumor microenvironment (TME), where adoptive T cells often encounter resident suppressive immune cell lineages. The administration of lymphodepleting conditioning in the form of chemotherapy, fludarabine/cyclophosphamide (FLU/CY) prior to the infusion of T cells is a critical step to ensure T cell engraftment and persistence. The addition of total body irradiation (TBI) to FLU/CY can further enhance lymphodepletion but comes at a cost of off-target toxicity. Thus, the use of an agent that can more selectively lymphodeplete may improve the efficacy of ACT without increased off-target toxicity. LLP2A is a peptidomimetic small molecule with a high affinity for very late antigen- 4 (VLA-4), expressed at high levels in lymphocytes and several cancers including melanoma and neuroblastoma. Here, we propose to test VLA-4–targeted 67Cu-LLP2A radionuclide therapy (TRT) as a single agent or in combination with dose-reduced (DR)-FLU/CY prior to ACT in two syngeneic solid tumor models (pmel-1/hgp100 B16 melanoma and GD2 CAR/NXS-2 neuroblastoma model). We hypothesize that the combination of 67Cu-LLP2A + DR-FLU/CY is a more effective lymphodepleting regimen than FLU/CY alone (Hypothesis 1). We also hypothesize that 67Cu-LLP2A TRT can reduce tumor burden through direct radiation- induced cell death and can facilitate T-cell mediated killing. We hypothesize that this new 67Cu-LLP2A conditioning regimen will extend the survival of mice with VLA-4–expressing solid tumors treated with ACT through greater penetration and activity of adoptive T cells within solid tumors (Hypothesis 2). To prove this, in Aim 1, we will use state-of-the-art dosimetry and biodistribution studies to determine the dose where 67Cu- LLP2A as a single agent or combined with DR-FLU/CY can achieve adequate lymphodepletion for ACT without causing toxicity as well reduce tumor burden through direct cytotoxic effects. Then in Aim 2, we will examine the ability of systemically administered 67Cu-LLP2A to enhance the efficacy of ACT in two syngeneic solid tumor models. After completion of these aims, we will demonstrate that 67Cu-LLP2A TRT has the potential to redefine current conditioning approaches for ACT and improve the outcomes of patients with solid tumors.

项目总结及摘要包括嵌合抗原受体 (CAR) T 细胞在内的过继性 T 细胞疗法 (ACT) 是新型免疫疗法取得了无与伦比的成功，特别是在白血病患者中，但它们在实体治疗中的疗效有限。成功的障碍之一是 ACT 穿透实体瘤微环境 (TME) 的能力，过继性 T 细胞经常遇到常驻抑制性免疫细胞谱系。术前以化疗、氟达拉滨/环磷酰胺 (FLU/CY) 的形式进行淋巴细胞清除调理 T细胞的输注是确保T细胞植入和持续存在的关键步骤。对 FLU/CY 进行照射 (TBI) 可以进一步增强淋巴细胞清除，但代价是脱靶毒性。因此，使用能够更选择性地清除淋巴细胞的药物可能会提高 ACT 的疗效，而无需 LLP2A 是一种对非常晚期抗原具有高亲和力的拟肽小分子。 4 (VLA-4)，在淋巴细胞和多种癌症（包括黑色素瘤和癌症）中高水平表达在这里，我们建议将 VLA-4 靶向 67Cu-LLP2A 放射性核素疗法 (TRT) 作为单一疗法进行测试。在两个同基因实体瘤模型中，在 ACT 之前使用药物或与剂量减少的 (DR)-FLU/CY 组合（pmel-1/hgp100 B16 黑色素瘤和 GD2 CAR/NXS-2 神经母细胞瘤模型）。 67Cu-LLP2A + DR-FLU/CY 组合是比单独使用 FLU/CY 更有效的淋巴清除方案（假设 1）我们还研究了 67Cu-LLP2A TRT 可以通过直接放射减少肿瘤负荷。我们发现这种新的 67Cu-LLP2A 可以诱导细胞死亡并促进 T 细胞介导的杀伤。预处理方案将延长接受 ACT 治疗的表达 VLA-4 实体瘤的小鼠的生存期通过实体瘤内过继性 T 细胞的更大渗透和活性（假设 2）。目标 1，我们将使用最先进的剂量测定和生物分布研究来确定 67Cu- LLP2A 作为单一药物或与 DR-FLU/CY 联合使用，可以实现 ACT 所需的充分淋巴细胞清除，而无需毒性以及通过直接细胞毒性作用减少肿瘤负荷然后在目标 2 中我们将检查。系统施用 67Cu-LLP2A 增强 ACT 在两种同源固体中的功效的能力完成这些目标后，我们将证明 67Cu-LLP2A TRT 有潜力重新定义当前的 ACT 调理方法并改善实体瘤患者的治疗结果。