Novel Strategies for Cancer Immunotherapy in Stem Cell Transplant

干细胞移植中癌症免疫治疗的新策略

• 批准号: 8403819
• 负责人: Yiping Yang
• 金额: $ 29.52万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403819
• 关键词: Allogenic; Antigen Presentation Pathway; Autologous; Biological Process; CD8B1 gene; Cancer Vaccines; Cell Transplants; Cells; Dendritic Cell Vaccine; Elements; Generations; Health; Hematopoietic; IL2RA gene; Immune; Immune system; Immunity; Immunosuppressive Agents; Immunotherapeutic agent; Inflammatory; Interferon Type I; Lead; Learning; Life; Ligands; Malignant Neoplasms; Mediating; Myeloablative Chemotherapy; Natural Immunity; Pathway interactions; Production; Receptor Signaling; Recovery; Regulatory T-Lymphocyte; Residual Neoplasm; Stem cell transplant; T cell response; T memory cell; T-Lymphocyte; TLR2 gene; Testing; Toll-like receptors; Transplantation; Tumor Antigens; Tumor Immunity; Vaccination; Vaccines; Vaccinia virus; Work; base; cancer immunotherapy; cytokine; design; in vivo; novel; novel strategies; tumor

DESCRIPTION (provided by applicant): Tumor-induced immune evasion represents one chief barrier in cancer immunotherapy. The mechanisms underlying this immune evasion include defective tumor-antigen processing and presentation, production of immune inhibitory cytokines, and induction of tumor-specific T cell tolerance mediated by CD4+CD25+ regulatory T (TReg) cells. Myeloablative chemotherapy with stem cell transplant may offer the best chance of achieving a state of minimal residual disease, and thus minimizing tumor-induced immune evasion. However, TReg-mediated tumor-specific T cell tolerance persists following transplant. We have identified that in vivo stimulation of Toll-like receptors (TLRs) of the innate immunity is required for the reversal of TReg-mediated suppression on tumor-specific CD8+ T cells post-transplant. This can be achieved by conventional dendritic cell (cDC) vaccines co-administered with a TLR9 ligand, CpG in vivo. We have also discovered that vaccinia virus (VV)-based vaccines can even more potently activate tumor-specific CD8 T cell response post-transplant due to their unique ability to activate multiple innate immune pathways in vivo: VV activates cDCs through TLR2, leading to the production of pro-inflammatory cytokines, and a TLR-independent pathway, resulting in secretion of type I interferons (IFNs); In addition, VV also activates plasmacytoid DCs (pDCs) to secrete high levels of type I IFNs in a TLR-dependent manner. Taken together, these observations suggest a central hypothesis that efficient activation of innate immune system is critical for overcoming TReg-mediated suppression on tumor- specific T cells through post-transplant vaccinations. To test this hypothesis, we propose to pursue the following 5 aims: 1) To study the biological function of pDCs in TLR-dependent augmentation of anti-tumor immunity post-transplant; 2) To delineate the mechanism(s) underlying TLR-dependent reversal of TReg-mediated suppression on tumor-specific T cells post-transplant; 3) To investigate the synergistic effect of multiple TLRs on the generation of anti-tumor effector and long-lived memory T cells post-transplant; 4) To determine the function of TLRs in the recovery of innate immune cells post-transplant; 5) To evaluate the efficacy of novel immunotherapeutic strategies for treating pre-established tumors in the setting of stem cell transplant. We expect that this work will lead to the identification of critical elements for enhancing anti-tumor T cell immunity post-transplant, and in turn will help us design new generations of effective tumor vaccines in the setting of stem cell transplant.

描述（由申请人提供）：肿瘤诱导的免疫逃避是癌症免疫疗法的一个主要障碍。这种免疫逃避的基础机制包括肿瘤 - 抗原加工和表现，免疫抑制细胞因子的产生以及诱导由CD4+ CD25+调节性T（Treg）细胞介导的肿瘤特异性T细胞耐受性。干细胞移植的骨髓性化学疗法可能提供了达到最小残留疾病状态的最佳机会，从而最大程度地减少了肿瘤诱导的免疫逃避。然而，移植后Treg介导的肿瘤特异性T细胞耐受性持续存在。我们已经确定，在移植后肿瘤特异性CD8+ T细胞上逆转Treg介导的抑制作用是对先天免疫力的Toll样受体（TLR）的体内刺激。这可以通过与TLR9配体在体内CpG共同采用的常规树突状细胞（CDC）疫苗可以实现。 We have also discovered that vaccinia virus (VV)-based vaccines can even more potently activate tumor-specific CD8 T cell response post-transplant due to their unique ability to activate multiple innate immune pathways in vivo: VV activates cDCs through TLR2, leading to the production of pro-inflammatory cytokines, and a TLR-independent pathway, resulting in secretion of type I interferons （IFNS）;此外，VV还激活静态晶状体DC（PDC）以TLR依赖性方式分泌I型IFN的高水平。综上所述，这些观察结果表明，有效激活先天免疫系统对于通过移植后疫苗接种来克服对肿瘤特异性T细胞的抑制至关重要。为了检验这一假设，我们建议追求以下5个目标：1）研究PDC在TLR依赖性增强抗肿瘤免疫后的生物学功能； 2）描述了TREG介导的抑制在移植后肿瘤特异性T细胞上的TLR依赖性逆转的机制； 3）研究多个TLR对抗肿瘤效应子和移植后长寿命的记忆T细胞产生的协同作用； 4）确定TLR在移植后先天免疫细胞恢复中的功能； 5）评估新型免疫治疗策略在干细胞移植中治疗预先建立的肿瘤的功效。我们预计这项工作将导致鉴定移植后抗肿瘤T细胞免疫的关键元素，进而帮助我们在干细胞移植的情况下设计新一代有效的肿瘤疫苗。