T Cell Therapy Targeting LMP1 and 2 in EBV+VE Lymphomas

EBV VE 淋巴瘤中靶向 LMP1 和 2 的 T 细胞疗法

• 批准号: 7253725
• 负责人: Stephen Gottschalk
• 金额: $ 24.42万
• 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 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7253725
• 关键词: Adenovirus Vector; Adopted; Adoptive Transfer; Animal Model; Antigen-Presenting Cells; Antigens; Antitumor Response; Antiviral Agents; Autologous; B-Cell Lymphomas; Biological Assay; Blood specimen; CD45 Antigens; Cell Line; Cell Proliferation; Cells; Clinical; Clinical Research; Clinical Trials; Clone Cells; Cytokine Inducible SH2-Containing Protein; Cytotoxic T-Lymphocytes; EBV-associated malignancy; Effectiveness; Ensure; Epstein-Barr Virus Infections; Escape Mutant; Goals; HLA-A2 Antigen; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Home environment; Human Herpesvirus 4; Image; Immune; Immune response; Immune system; Immunity; Immunotherapy; In complete remission; Infusion procedures; Interleukin-12; Interleukin-15; LMP1; Label; Localized; Lymphocyte; Lymphoid; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Marrow; Measures; Methods; Modeling; Monitor; Monoclonal Antibodies; Mus; Myeloid Cells; Non-Hodgkin' s Lymphoma; Numbers; Outcome; Patients; Phase; Phase I Clinical Trials; Production; Progressive Disease; Recurrent disease; Refractory; Relapse; Research; Research Personnel; Resolution; Safety; Signal Transduction; Small Interfering RNA; Specificity; Staging; Staining method; Stains; Standards of Weights and Measures; Symptoms; T-Cell Activation; T-Cell Lymphoma; T-Cell Proliferation; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Training; Transgenic Animals; Treatment Protocols; Tumor Tissue; Vaccinated; Vaccination; Vaccines; Viral Antigens; Viral Proteins; Virus; cancer cell; clinically relevant; cytokine; improved; in vivo; neoplastic cell; outcome forecast; peripheral blood; prevent; progenitor; reconstitution; response; tumor; vaccination strategy; viral DNA

Latent Epstein-Barr (EBV) infection is associated with both Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL), and EBV antigens expressed in these lymphomas are potential targets for immunotherapy. Although clinical studies with EBV-specific cytotoxic T cells (CTLs) have yielded promising results, their antilymphoma activity is limited by several factors. For example, 1) EBV-specific CTL lines generated by standard methods are dominated by T-cell clones not reactive to the subdominant EBV proteins LMP1 and LMP2 expressed in HD and NHL and 2) infused EBV-specific CTLs do not significantly expand in vivo after adoptive transfer. Our central hypothesis is that by overcoming these limitations, we will enhance the antitumor activity of EBV-specific CTLs and improve clinical outcome in lymphoma patients treated with these cells. To demonstrate the feasibility of this strategy, we propose three specific research aims. AIM 1: We will infuse LMP1- and LMP2-specific CTLs into EBV-positive HD or NHL patients to generate the broadest possible CTL response against the malignant cells, and to ensure that suitable CTL epitopes are available, regardless of the patient's HLA type. AIM 2: We have shown that the infusion of monoclonal antibodies targeting the CD45 antigen results in transient lymphodepletion and enhanced EBV- specific CTL expansion. We will build on these findings and test in an animal model the ability of different vaccines to further enhance the proliferation of adoptively transferred CTLs post lymphodepletion. We hypothesize that the expression of IL-15 or the silencing of SOCS1, in combination with LMP1 and LMP2 expression, will enhance the vaccine-induced proliferation and expansion of LMP1- and LMP2-specific CTLs administered to patients. Finally, in AIM 3, we will test in a second Phase I clinical trial the safety and effects of an optimized vaccine on the expansion, persistence and antitumor effector function of pre-existing or adoptively transferred LMP1- and LMP2-specific CTLs in HD or NHL patients with relapsed disease. Lay summary: The body's immune defenses against cancer are usually not effective because the cancer cells, by themselves, do not attract a strong immune response. Some lymphomas contain parts of the Epstein-Barr virus that do stimulate the immune system. We plan to collect T cells, a component of the immune system, from patients' blood samples and train them to recognize the LMP1 and LMP2 segments of the Epstein-Barr virus. After these cells are returned to the patient, they should attack and destroy the tumors cells that contain LMP1 and LMP2.

潜伏性eb病毒感染与霍奇金病（HD）和非霍奇金病相关