Overcoming Tumor Evasion in EBV+ve Lymphomas

克服 EBV 和淋巴瘤的肿瘤逃逸

• 批准号: 10000868
• 负责人: CLIONA M ROONEY
• 金额: $ 26.78万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000868
• 关键词: Adoptive Transfer; Antibodies; Antigen Receptors; Antigen Targeting; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Biological Assay; CD19 Antigens; CD19 gene; Cells; Clinical; Clinical Protocols; Clinical Trials; Data; Dinoprostone; Disease; Disease Marker; Disease remission; EBV specific T-cells; Engraftment; Ensure; Environment; Epitope spreading; Equilibrium; Frequencies; Goals; Hodgkin Disease; Homing; Human; Human Herpesvirus 4; IL7 gene; Image; Immune; Immune Evasion; Immunosuppression; Immunotherapy; Infusion procedures; Interleukin-15; Lead; Ligands; Link; Lymphoid Tissue; Lymphoma; Lymphoma cell; Measurement; Measures; Monitor; Non-Hodgkin' s Lymphoma; Outcome; Patients; Peer Review; Plasma; Pre-Clinical Model; Proliferating; Property; Proteins; Receptor Signaling; Recurrent disease; Refractory Disease; Reproducibility; Research; Resistance; Retroviral Vector; Safety; Signal Transduction; Site; Source; Stable Disease; T cell anergy; T cell therapy; T-Cell Activation; T-Cell Immunologic Specificity; T-Cell Proliferation; T-Lymphocyte; Testing; Time; Toxic effect; Transforming Growth Factor beta; Transgenes; Tumor Antigens; Tumor Escape; Tumor-Derived; Validation; Viral Antigens; Viral Genome; Viral Proteins; Writing; antigen binding; antigen-specific T cells; base; chimeric antigen receptor; curative treatments; cytotoxicity; design; disorder risk; exosome; experimental study; hazard; high risk; imaging study; immunogenic; in vivo; novel strategies; partial response; peripheral blood; pre-clinical; primary endpoint; response; safety and feasibility; standard measure; tumor; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY / ABSTRACT The broad goal of Project 3 is to devise and implement novel strategies of effective, low-toxicity EBV-specific T cell therapy for EBV-positive lymphomas, which account for approximately 40% of all human lymphomas. In a recent clinical trial of such immunotherapy in patients with high-risk active disease at the time of infusion of EBV-specific T cells (EBVSTs), we found that favorable tumor responses correlated with increased numbers of both EBVSTs and T cells that recognized nonviral tumor antigens (TAs), an example of antigen spreading. In most patients, however, the increases in both types of T cells were only transient, suggesting induction of T-cell anergy by potent immunosuppressive mechanisms in the tumor microenvironment. Thus, to prolong T cell expansion and function in this hostile setting, we are testing whether artificial costimulation by costimulatory chimeric antigen receptors (CoCARs) will enhance T cell proliferation and sustain EBVST activation in the face of inhibitory molecules. This approach, like that with classical CARs, combines the antigen binding domain of an antibody with costimulatory endodomains that trigger proliferation of the host T cell, but lacks the zeta chain of the TCR that is required to initiate cytotoxicity. The CoCAR therefore allows any cognate target cell to induce T cell costimulation without sustaining damage itself. CD19 was selected as the CoCAR target antigen because B cells are ubiquitous in lymphoid tissues and are often found within lymphoma sites; moreover, their function as professional antigen-presenting cells should enable them to enhance CoCAR signaling appreciably. The overarching hypothesis for this strategy – that appropriate stimulation by EBV antigens and CD19 will render CoCAR-expressing EBVSTs resistant to tumor-derived inhibitory molecules, promoting their expansion and persistence after infusion and thus greater antigen spreading and better tumor responses – will be tested in the following specific aims. AIM 1: Optimize in a preclinical model the CD19-specific CoCAR for use in human EBV-specific T cells . AIM 2: Evaluate the feasibility and safety of using EBVSTs modified with CD19-directed CoCARS to treat patients with EBV-associated Hodgkin lymphoma or non-Hodgkin lymphoma. AIM 3: Evaluate the expansion, persistence and antitumor activity of CoCAR-modified EBVSTs and TA- specific T cells, based on quantitative PCR measurements, ELIspot assay results, and imaging studies. Validation of this strategy may lead to its common use in the treatment of EBV-positive lymphoma.

项目摘要/摘要