Inflammation and Immunotherapy: Vaccines to treat cancer and Alzheimer's disease

炎症和免疫治疗：治疗癌症和阿尔茨海默病的疫苗

• 批准号: 8335927
• 负责人: Arya Biragyn
• 金额: $ 26.21万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 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/8335927
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease model; Antibodies; Antigens; Brain; Breast Cancer Cell; CC chemokine receptor 4; CCL17 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cancer Vaccines; Cell Nucleus; Cells; Clinical Trials; DNA; Dendritic Cells; Development; Disease; Elderly; Hepatitis B Surface Antigens; Housing; Human; Immune; Immune response; Immune system; Immunization; Immunotherapy; Impaired cognition; Impairment; Infiltration; Inflammation; Inflammatory; Interleukin-7; Laboratories; Laminin Receptor; Legal patent; Leukocytes; Link; Longevity; Lung; Lymphoid; Malignant Neoplasms; Mediating; Mus; Natural Killer Cells; Neoplasm Metastasis; Nerve Degeneration; Onset of illness; Paper; Pathway interactions; Patients; Peptide Vaccines; Phase; Pneumonia; Process; Production; Prognostic Marker; Reporting; Role; Surface; T cell response; T-Lymphocyte; TSLP gene; Testing; Therapeutic; Thymus Gland; Vaccines; Work; X Chromosome; age related; allergic response; arm; base; cancer cell; chemokine; clinical efficacy; combat; cytokine; embryonic antigen; human TSLP protein; improved; malignant breast neoplasm; novel; novel vaccines; particle; preclinical study; response; senescence; sperm protein; tumor; tumor growth; tumor progression

1) CCL17 is chemokine involved in recruitment of Th2-type cytokine-producing immune cells, including Tregs, acting through its receptor CCR4. Here, we found that primary breast cancer is responsible for the initial control of of metastasis. It induces production of CCL17 in the lungs lungs to facilitate co-recruitment of CCR4+ breast cancer cell and Tregs. The co-infiltration of Tregs is to protect the metastasizing cancer cells from NK cells in the lungs (see AG000443-04). Utilizing in house developed strategies, such as chemotoxin that depletes CCR4+ cells (see AG000444-04), we demonstrate that the approaches that target any part of this pathway can successfully interfere with cancer metastasis. This is a first report on the importance of TARC/CCR4 axis in the metastatic spread of breast cancer (Olkhanud et al., 2009; 2011). 2) Recently, we have found previously a novel mechanism that links pulmonary inflammation with breast cancer lung metastasis. We were among the first to demonstrate that breast cancer cells also utilize Thymic stromal lymphopoietin (TSLP, an IL-7-like type 1 cytokine that contributes to lymphoid development and promotes Th2-type allergic responses)to promote tumor progression and metastasis. The cancer-promoting activity of TSLP required CD4+ T cells to facilitate Th2-skewed immune responses whereas TSLP-stimulated dendritic cells had a negative effect on tumor growth. We propose that TSLP may be a cancer prognostic marker and that its targeting could have therapeutic potential (Biragyn & Leonard, Patent, pending). For example, the strategies that interfere with the expression of TSLP led to the dramatic decrease in tumor size and metastasis. 3) In this part of the work we wanted to test whether the inactivation of regulatory immune cells such as tBregs (the cells originally discovered in my laboratory) or suppressive factors (such as TARC and TSLP) would improve efficacy of our cancer vaccines. The first part of this work, the development of potent and simple cancer vaccines, has been successfully achieved. For example, we created chemokine-based novel vaccine strategy that was reported in several our papers (Biragyn et al. 1999; 2001; 2002, 2004; 2007; Schiavo et al., 2006). The breadth of the chemokine-based vaccines are in their ability to efficiently utilize the MHC processing pathways to elicit CD4+ T helper and CD8+ T cell responses (Biragyn et al., 2006; Schiavo et al., 2006). As a result, we have created two chemokine-based vaccine for human use: 1) The vaccine that targets an embryonic antigen OFA-iLRP (a highly conserved the 37-kDa oncofetal immature laminin receptor, that is specifically and highly expressed in a number of human malignancies) and 2) The SPANX-B -targeting vaccine. SPANX-B (a sperm protein associated with the nucleus on the chromosome X B) is a novel antigen with unknown function. The preclinical study of the OFA-iLPR vaccine was completed and reported (Biragyn et al., 2007; Patent, pending) it is ready to be tested in human clinical trials. We also reported clinical efficacy of SPANX-B using healthy humans leukocytes. We found that humans contain detectable amounts of circulating SPANX-B -specific T cell precursors that could be readily expanded to generate both helper CD4+ T cells and cytolytic CD8+ T cells (Almanzar et al., 2009; Biragyn and Larionov, Patent, pending). Encouraged by these results, recently we started the second phase of the work to test the role of regulatory immune cells, such as tBregs and Tregs, or suppressive factors (TSLP and CCL17) in the modulation of vaccine responses. 4) Alzheimer's disease (AD) is an incurable and progressive neurodegenerative senile disorder associated with the brain accumulation of Ab plaques. Although vaccines that reduce Ab plaques can control AD, the rationale for their use at the onset of the disease remains debatable. Old humans and mice usually respond ppoorly to vaccines due to presumably age-related immunological impairments. Here, we report that, by modifying vaccines, the poor responsiveness of old mice can be reversed. Unlike Ab peptide vaccine, DNA immunizations with the amino-terminal Ab(1-11) fragment exposed on the surface of HBsAg particles elicit high levels of anti-Ab antibody both in young and old mice. Importantly, in AD model 3xTgAD mice, the vaccine reduced Ab plaques, ameliorated cognitive impairments and, surprisingly, significantly increased life span. Hence, we propose that vaccines targeting Ab(1-11) can efficiently combat AD-induced pathological alterations and provide survival benefit in patients with AD (Olkhanud et al., 2011, submitted).

1) CCL17 是一种趋化因子，参与募集 Th2 型细胞因子产生的免疫细胞（包括 Tregs），通过其受体 CCR4 发挥作用。在这里，我们发现原发性乳腺癌负责转移的初始控制。它诱导肺部产生 CCL17，以促进 CCR4+ 乳腺癌细胞和 Tregs 的共同招募。 Tregs 的共同浸润是为了保护转移癌细胞免受肺部 NK 细胞的侵害（参见 AG000443-04）。利用内部开发的策略，例如消耗 CCR4+ 细胞的趋化毒素（参见 AG000444-04），我们证明针对该途径任何部分的方法可以成功干扰癌症转移。 这是关于 TARC/CCR4 轴在乳腺癌转移扩散中的重要性的第一份报告（Olkhanud 等，2009；2011）。 2）最近，我们之前发现了一种将肺部炎症与乳腺癌肺转移联系起来的新机制。我们是最早证明乳腺癌细胞也利用胸腺基质淋巴细胞生成素（TSLP，一种类似 IL-7 的 1 型细胞因子，有助于淋巴管发育并促进 Th2 型过敏反应）来促进肿瘤进展和转移的细胞之一。 TSLP 的促癌活性需要 CD4+ T 细胞来促进 Th2 倾斜的免疫反应，而 TSLP 刺激的树突状细胞对肿瘤生长有负面影响。我们认为 TSLP 可能是一种癌症预后标志物，并且其靶向可能具有治疗潜力（Biragyn & Leonard，专利，正在申请中）。例如，干扰 TSLP 表达的策略导致肿瘤大小和转移显着减小。 3) 在这部分工作中，我们想要测试调节性免疫细胞（例如 tBregs（最初在我的实验室发现的细胞）或抑制因子（例如 TARC 和 TSLP））的失活是否会提高我们的癌症疫苗的功效。这项工作的第一部分，即有效且简单的癌症疫苗的开发，已经成功实现。例如，我们创建了基于趋化因子的新型疫苗策略，该策略在我们的几篇论文中进行了报道（Biragyn 等人，1999 年；2001 年；2002 年、2004 年；2007 年；Schiavo 等人，2006 年）。基于趋化因子的疫苗的广度在于它们能够有效地利用 MHC 加工途径来引发 CD4+ T 辅助细胞和 CD8+ T 细胞反应（Biragyn 等人，2006 年；Schiavo 等人，2006 年）。因此，我们创建了两种基于趋化因子的人类疫苗：1) 靶向胚胎抗原 OFA-iLRP（一种高度保守的 37-kDa 癌胎儿未成熟层粘连蛋白受体，在多种人类恶性肿瘤中特异性且高度表达）的疫苗和 2) SPANX-B 靶向疫苗。 SPANX-B（一种与 X B 染色体上的细胞核相关的精子蛋白）是一种功能未知的新型抗原。 OFA-iLPR 疫苗的临床前研究已完成并报告（Biragyn 等人，2007 年；专利，正在申请中），已准备好在人体临床试验中进行测试。 我们还报告了使用健康人类白细胞进行 SPANX-B 的临床疗效。我们发现人类含有可检测量的循环 SPANX-B 特异性 T 细胞前体，这些前体可以很容易地扩增以产生辅助 CD4+ T 细胞和细胞溶解性 CD8+ T 细胞（Almanzar 等，2009；Biragyn 和 Larionov，专利，正在申请中）。 受到这些结果的鼓舞，最近我们开始了第二阶段的工作，以测试调节性免疫细胞（例如 tBreg 和 Tregs）或抑制因子（TSLP 和 CCL17）在调节疫苗反应中的作用。 4) 阿尔茨海默氏病（AD）是一种无法治愈的进行性神经退行性老年性疾病，与大脑中抗体斑块的积聚有关。尽管减少抗体斑块的疫苗可以控制 AD，但在疾病发作时使用疫苗的理由仍然存在争议。老年人和小鼠通常对疫苗反应不佳，原因可能是与年龄相关的免疫损伤。在这里，我们报告说，通过修改疫苗，可以逆转年老小鼠的不良反应性。与 Ab 肽疫苗不同，使用暴露在 HBsAg 颗粒表面的氨基末端 Ab(1-11) 片段进行 DNA 免疫，可在年轻和年老小鼠中引发高水平的抗 Ab 抗体。重要的是，在 AD 模型 3xTgAD 小鼠中，疫苗减少了抗体斑块，改善了认知障碍，并且令人惊讶的是，显着延长了寿命。因此，我们建议针对 Ab(1-11) 的疫苗可以有效对抗 AD 引起的病理改变，并为 AD 患者提供生存益处（Olkhanud 等人，2011 年提交）。