Artif. Antigen Presentation to Sensitize Virus-Spec. TCells for Adoptive Immunoth

阿蒂夫。

• 批准号: 7432449
• 负责人: Richard John O'REILLY
• 金额: $ 36.13万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7432449
• 关键词: Acquired Immunodeficiency Syndrome; Adopted; Adoptive Immunotherapy; Adoptive Transfer; Alleles; Allogenic; Allografting; Antigen Presentation; Antigen-Presenting Cells; Antigens; Antiviral Agents; Autologous; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; CD8B1 gene; CMV pp65 Peptide; Cells; Class; Clinical Trials; Colon Carcinoma; Conduct Clinical Trials; Cytomegalovirus; Dendritic Cells; Disease; Dose; Epitope Mapping; Epitopes; Epstein-Barr Virus Infections; FUS-1 Protein; Generations; Helper-Inducer T-Lymphocyte; Human Herpesvirus 4; Immunity; Immunocompromised Host; Immunotherapy; In Vitro; Infection; Infection prevention; Inherited; Langerhans cell; Length; Lymphoma; Malignant Epithelial Cell; Marrow; Morbidity - disease rate; Organ Transplantation; Other Therapy; Patients; Peptides; Phase; Phase II Clinical Trials; Positron-Emission Tomography; Pre-Clinical Model; Process; Proteins; Public Health; Resistance; Risk; SCID Mice; Specificity; T-Lymphocyte; Transcript; Viral; Viral Antigens; Viral Proteins; Viremia; Virus; Virus Diseases; Work; Xenograft procedure; cellular transduction; cytokine; cytotoxic; desire; embryo/fetus antigen; immunogenic; in vivo; migration; mortality; neoplastic cell; novel; novel strategies; reconstitution; response; tumor; virucide

CMV infections continue to be a major cause of morbidity and mortality in marrow allograft recipients, particularly recipients of HLA disparate grafts who often have delayed or dysfunctional reconstitution of T cell immunity. This project proposes to develop and evaluate novel strategies, incorporating artificial antigen-presenting cells (AAPCs) transduced to express a single HLA class I or class II allele and to express, process and present immunogenic peptides of the CMV protein pp65, to generate CMV-virus specific T cells for adoptive immunotherapy. The objective of this experimental work is to develop a rapid, practicable and broadly applicable approach for the generation of donor-derived CD8+ cytotoxic and CD4* helper T cells specific for immunogenic proteins of CMV for adoptive transfer to treat or prevent infection following allogeneic marrow or organ transplantation. The project includes four specific aims. In Specific Aim 1. a panel of AAPCs expressing single common HLA class I and II alleles and CMV-pp65 will be developed and their capacity to elicit pp65 specific viricidal T cell responses assessed in comparison to CMV-pp65 autologous Langerhans cells and CMV peptide loaded dendritic cells. In Specific Aim 2, we will adopt a novel epitope mapping strategy to identify the spectrum of CMV-pp65 peptides recognized by CD8+ and CD4+ T cells sensitized with the AAPCs in comparison with these autologous APCs. In so doing, we will explore the hypothesis that this combined strategy may provide a consistent approach for identifying and discriminating epitopes that are naturally presented and can elicit functional virus-specific T cell responses. In Specific Aim 3. we will evaluate, in an informative preclinical model, the migration, target accumulation and antigen-specific function of CMV-pp65 peptide-specific CD4+ and CDS* T cells following adoptive transfer into NOD/SCID mice bearing colon carcinoma and lymphoma xenografts transduced to express CMV-pp65. Lastly, in Specific Aim 4. we propose to conduct two clinical trials. The first is a phase II expansion of a trial evaluating donor T cells transduced with NIT early after in vivo sensitization to EBV for the treatment of EBV lymphomas complicating marrow allografts. This trial will incorporate PET imaging of HSV-TK+ NIT+ T cells in vivo with [124I]-FIAU. The second trial will evaluate T cells sensitized with CMV-pp65-AAPC in the treatment of patients with persistent antigenemia at risk for CMV disease. We hypothesize that panels of these novel immediately accessible and replenishable AAPCs will permit a more rapid, consistently effective and practicable approach for generating virus- specific T cells of desired specificity and HLA restriction for adoptive immunotherapy of severe CMV infections. As to the relevance to Public Health, this approach, if successful, may also provide practicable strategies for generating T cells for adoptive therapy of other severe viral infections in immunocompromised hosts, including patients with AIDS and for treatment of tumors differentially expressing fetal antigens or fusion proteins.

CMV感染仍然是同种异体受体发病率和死亡率的主要原因，尤其是 HLA不同移植物的接受者通常会延迟或功能失调的T细胞免疫重建。这个项目 提议制定和评估新型策略，结合人工抗原细胞（AAPC）转导 表达单个HLA I类或II类等位基因，并表达，处理和呈现CMV的免疫原性肽 蛋白质pp65，生成用于过养免疫疗法的CMV病毒特异性T细胞。这个实验的目的 工作是为了生成供体衍生的CD8+的快速，可行且广泛适用的方法 细胞毒性和CD4*辅助T细胞针对CMV的免疫原性蛋白，用于处理或预防 同种异性骨髓或器官移植后的感染。该项目包括四个具体目标。在特定目标1中。 将开发一组单一常见的HLA I和II等位基因和CMV-PP65的AAPC，并将开发它们 与CMV-PP65自体Langerhans相比，评估的PP65特异性病毒T细胞反应的能力 细胞和CMV肽加载的树突状细胞。在特定目标2中，我们将采用一种新颖的表位映射策略 确定由CD8+和CD4+ T细胞识别的CMV-PP65肽的光谱 与这些自体APC进行比较。这样，我们将探讨以下假设 提供一种一致的方法来识别和区分自然呈现的表位，并可以引起 功能病毒特异性T细胞反应。在特定目标3中。我们将在信息丰富的临床前模型中评估 CMV-PPP65肽特异性CD4+和CDS* T细胞的迁移，目标积累和抗原特异性功能 在继承后转移到携带结肠癌和淋巴瘤异种移植的点头/SCID小鼠中。 Express CMV-PP65。最后，在特定目标4中。我们建议进行两项临床试验。第一个是II期扩展 在体内敏化对EBV的EBV治疗后，评估用NIT转导的供体T细胞的试验 淋巴瘤使同种异体移植复杂化。该试验将在体内纳入HSV-TK+ NIT+ T细胞的PET成像与 [124i] -fiau。第二项试验将评估与CMV-PPP65-AAPC敏化的T细胞在治疗患者中 持续性抗原血症患有CMV疾病的风险。我们假设这些小说的面板立即可访问，并且 可补充的AAPC将允许采用更快，始终如一的有效和可行的方法来生成病毒 - 具有所需特异性和HLA限制的特定T细胞对严重CMV感染的过继免疫疗法。至于 与公共卫生相关，这种方法（如果成功）也可能提供可行的策略来产生 通过免疫功能低下的宿主中其他严重病毒感染的过养细胞，包括艾滋病患者 并用于治疗差异表达胎儿抗原或融合蛋白的肿瘤。