Personalized Adoptive T-cell Therapy for AML

AML 的个性化过继 T 细胞治疗

基本信息

批准号：
10438900
负责人：
DAVID E AVIGAN
金额：
$ 71.71万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10438900
关键词：
Adoptive Immunotherapy Adoptive Transfer Age Antigen Targeting Antigen-Presenting Cells Antigens Area Autologous Autologous Dendritic Cells Beds Biological Markers Bone Marrow CD28 gene CD3 Antigens Cancer Vaccines Cell fusion Cells Cellular immunotherapy Characteristics Clinical Research Clonal Expansion Clone Cells Correlation Studies Dendritic Cells Development Disease Disease remission Effector Cell Elements Fostering Functional disorder Generations Hematopoietic Heterogeneity IL7 gene Immune Immunocompetent Immunologic Surveillance Individual Infiltration Infusion procedures Interleukin-15 Investigation Leukemic Cell Ligation MADH2 gene Malignant - descriptor Malignant lymphoid neoplasm Mediating Mediator of activation protein Memory Modeling Mus Nature Pathway interactions Patients Phase I Clinical Trials Phase II Clinical Trials Phenotype Population Recurrence Relapse Reporting T cell therapy T-Cell Activation T-Lymphocyte Time Toxic effect Transforming Growth Factor beta Translating Tumor-Derived Vaccination Vaccine Therapy Vaccines antigen-specific T cells chemokine chemotherapy chimeric antigen receptor T cells design exhaust exhaustion follow-up immunogenicity in vivo leukemia long term memory migration neoantigens neoplastic cell novel novel strategies peripheral blood phase 1 study pre-clinical prevent response restoration senescence transcriptome tumor tumor heterogeneity tumor microenvironment vaccine efficacy vaccine platform vaccine response vaccine strategy

项目摘要

Abstract/Project Summary The development of strategies to expand and activate AML specific T cells is of critical importance. We have developed a personalized cancer vaccine in which patient derived tumor cells are fused with autologous dendritic cells (DCs), presenting a broad array of antigens that capture the heterogeneity of the leukemia cell population, including shared and neoantigens. We have completed a phase II clinical trial in which patients that achieve remission following chemotherapy undergo serial vaccination with DC/AML fusions. Remarkably, despite a median age of 63, 71% remained free of disease with a median follow up of 5 years. Vaccination was associated with the expansion of T cells targeting both autologous AML cells and leukemia associated antigens. The DC/AML vaccine can be used as a platform to generate activated leukemia-specific T cells ex- vivo for adoptive immunotherapy. In this way, effector cells may be generated that are leukemia specific, capture tumor heterogeneity, and are activated ex vivo to achieve a functionally competent phenotype. We have demonstrated that vaccine stimulation in the context of IL7/IL-15 results in enhanced levels of central memory cells critical for long term persistence of response. While the generation of vaccine stimulated leukemia specific T cells ex vivo represents a promising strategy to effectively target AML cells in vivo, the immunosuppressive nature of the tumor microenvironment remains a barrier to the development of a memory response and long-term protection. We performed transcriptome analysis in the remission bone marrow at time of vaccination to identify biomarkers that were predictive of durable response as compared to early relapse following vaccination with DC/AML fusions. Of note, decreased expression of TGF-β in the bone marrow microenvironment was associated with durable remission. These results are consistent with prior reports suggesting TGF-β as a negative regulator of tumor immunogenicity, T cell activation and infiltration into the tumor bed. As such there is strong rationale to target TGFβ to enhance vaccine efficacy. In the present study, we will create a novel strategy for adoptive T cell therapy generated by vaccine mediated stimulation, selection of antigen specific T cells and ex vivo expansion. Functional characteristics will be examined in an immunocompetent murine leukemia model. We will then examine the effect of TGF-β inhibition on vaccine response and TGF inhibition within vaccine stimulated T cells by silencing of the downstream effector SMAD2. In the second aim, the T cell product will be characterized with respect to targeting of shared and neo-antigen targets, oligoclonal expansion and diversity of the repertoire, expression of markers of activation, exhaustion, senescence, and chemokines needed for migration into the tumor bed. In the third aim, we will conduct a Phase I study in which patients with AML who achieve complete remission will undergo adoptive therapy with vaccine stimulated T cells.

摘要/项目摘要开发扩大和激活 AML 特异性 T 细胞的策略至关重要。开发了一种个性化癌症疫苗，其中患者来源的肿瘤细胞与自体肿瘤细胞融合树突状细胞 (DC)，呈现多种抗原，可捕获白血病细胞的异质性人群，包括共享抗原和新抗原，我们已经完成了一项 II 期临床试验，其中患者值得注意的是，化疗后接受 DC/AML 融合疫苗连续接种后获得缓解。尽管中位年龄为 63 岁，但在中位随访 5 年的情况下，71% 的人仍然没有患病。与针对自体 AML 细胞和白血病的 T 细胞扩增相关 DC/AML 疫苗可用作生成活化的白血病特异性 T 细胞的平台。通过这种方式，可以产生白血病特异性的效应细胞。捕获肿瘤异质性，并在离体激活以实现功能上合格的表型。已经证明，在 IL7/IL-15 的背景下进行疫苗刺激会导致中枢神经系统水平的增强。当疫苗的产生受到刺激时，记忆细胞对于长期持续的反应至关重要。离体白血病特异性 T 细胞代表了一种在体内有效靶向 AML 细胞的有前途的策略，肿瘤微环境的免疫抑制性质仍然是记忆发展的障碍我们在缓解期骨髓中进行了转录组分析。疫苗接种时间以确定与早期相比可预测持久反应的生物标志物值得注意的是，骨中 TGF-β 的表达降低。骨髓微环境与持久缓解相关，这些结果与之前的结果一致。报告表明 TGF-β 作为肿瘤免疫原性、T 细胞活化和浸润的负调节因子因此，有充分的理由以 TGFβ 为靶点来增强疫苗功效。在目前的研究中，我们将创建一种新的策略，用于通过疫苗介导产生的过继性 T 细胞疗法刺激、抗原特异性T细胞的选择和离体扩增的功能特征。然后我们将在免疫活性小鼠白血病模型中检查 TGF-β 抑制的效果。通过下游沉默对疫苗刺激 T 细胞内的疫苗反应和 TGF 抑制产生影响在第二个目标中，T 细胞产品将针对共享的靶向进行表征。和新抗原靶标、寡克隆扩增和库的多样性、标记物的表达在第三个目标中，激活、耗尽、衰老和迁移到肿瘤床所需的趋化因子。我们将进行一项 I 期研究，其中获得完全缓解的 AML 患者将接受使用疫苗刺激的 T 细胞进行过继治疗。