Neuroimmunology of Vaccines in Adoptive T-cell Therapy for Brain Tumor

脑肿瘤过继 T 细胞疗法中疫苗的神经免疫学

基本信息

批准号：
7808668
负责人：
JOHN H. SAMPSON
金额：
$ 23.55万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7808668
关键词：
Accounting Active Immunotherapy Adjuvant Adoptive Immunotherapy Adult Adverse effects Antigens Astrocytoma Autoimmune Process Autoimmunity Brain Neoplasms Cancer Etiology Cell Maintenance Cell Therapy Cessation of life Child Clinical Clinical Research Clinical Trials Combined Vaccines Coupled Cyclophosphamide Data Dendritic Cell Vaccine Dendritic Cells Dose Engraftment Excision Experimental Autoimmune Encephalomyelitis Frequencies Glioblastoma Goals Half-Life Hematopoietic Human Immune response Immunity Immunotherapy Interleukin-15 Interleukin-2 Interleukin-7 Lymphocyte Lymphocyte Count Lymphopenia Maintenance Malignant - descriptor Mediating Medical Modeling Mus Operative Surgical Procedures Opportunistic Infections Patients Population Primary Brain Neoplasms Quality-Adjusted Life Years RNA Radiation therapy Recovery Regimen Risk Safety Specificity Supplementation T memory cell T-Cell Receptor T-Lymphocyte Therapeutic Toxic effect Transgenic Organisms Translating Tumor Antigens United States Vaccination Vaccines Whole-Body Irradiation chemotherapy cytokine design improved in vivo innovation interest killings melanoma neoplastic cell neuroimmunology neurotoxicity novel novel strategies public health relevance response temozolomide tumor vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): The most common malignant primary brain tumor, glioblastoma (GBM), remains uniformly fatal despite surgical resection, incapacitating radiation therapy, and myelodepleting temozolomide (TMZ) chemotherapy. Adjuvant immunotherapy promises to induce robust tumor-specific immune responses that eliminate neoplastic cells with unparalleled specificity, but TMZ-induced lymphopenia would be expected to curtail the induction and persistence of productive antitumor immune responses. However, following periods of lymphopenia, such as those induced by TMZ, there is a homeostatic proliferation of remaining lymphocytes. Thus, T-cells that predominate during this recovery period have a competitive advantage and may become disproportionately over-represented in the recovering lymphocyte population. We and others have identified this as an opportunity to enhance the preferential expansion and maintenance of ex vivo expanded and adoptively transferred anti-tumor T-cells. While high-dose IL-2 has been utilized in most human clinical trials of adoptive immunotherapy for maintenance and expansion of transferred lymphocytes, recent studies in murine models have demonstrated capacity to achieve T cell maintenance and anti-tumor efficacy using in vivo vaccination in the absence of exogenous cytokine supplementation. Given the documented neurotoxicity of IL-2 in patients with GBM, the capacity to facilitate in vivo engraftment of tumor-specific lymphocytes using concomitant vaccination is of paramount interest. Furthermore, our preliminary data demonstrate that vaccines given during the recovery from TMZ-induced lymphopenia result in dramatically enhanced humoral responses and antigen- specific T-cell frequencies in mice and humans. Although our preliminary data uses T-cells from mice with transgenic T-cell receptors to evaluate the combination of vaccine and adoptive immunotherapy in the context of TMZ, such approaches are not easily translated into human studies. Dendritic cells (DCs) loaded with the total antigenic content of tumor cells in the form of RNA (TTRNA), however, provide an innovative strategy that we and others have safely and successfully to expand tumor-specific lymphocytes against a broad repertoire of tumor antigens. Our OVERALL GOAL then is to evaluate the combination of adoptive cellular therapy and TTRNA-loaded DC vaccines during recovery from serial lymphodepletion with TMZ in a murine brain tumor model prior to clinical studies in humans. PUBLIC HEALTH RELEVANCE: Treatment for brain tumors represents the most expensive medical therapy per quality-adjusted life-year saved currently provided in the United States, and brain tumors remain the most common cause of cancer death among children and account for more deaths in adults than melanoma. Vaccines are an attractive adjuvant approach to therapy for these tumors, but are thwarted by the chemotherapy used for these tumors that kills lymphocytes that might respond to these vaccines. This effect of the chemotherapy, however, actually helps maintain anti-tumor lymphocytes infused immediately after the chemotherapy so we will evaluate the combined efficacy of vaccines and transferred antitumor lymphocytes in this proposal.

描述（由申请人提供）：尽管手术切除，无能为力，放射治疗和骨髓脱死替莫唑胺（TMZ）化学疗法，但最常见的恶性原发性脑肿瘤（GBM）仍然是致命的。辅助免疫疗法有望诱导强大的肿瘤特异性免疫反应，以无与伦比的特异性消除肿瘤细胞，但预计TMZ诱导的淋巴细胞减少症会减少生产性抗肿瘤免疫反应的诱导和持久性。然而，随后的淋巴细胞减少症（例如TMZ诱导的淋巴细胞），剩余的淋巴细胞会体内稳态增殖。因此，在此恢复期间占主导地位的T细胞具有竞争优势，并且在恢复淋巴细胞种群中可能会过分代表。我们和其他人将其确定为增强离体扩展和传递转移的抗肿瘤T细胞的优先扩展和维护的机会。虽然大多数人类的收养免疫疗法临床试验都使用了大剂量IL-2来维持和扩展转移的淋巴细胞，但在鼠模型中，最近在鼠模型中进行的研究表明，在缺乏源自细胞因子的情况下，使用体内疫苗接种实现T细胞维持和抗肿瘤疗效的能力。鉴于IL-2在GBM患者中的神经毒性的记录，使用伴随疫苗接种的体内植入肿瘤特异性淋巴细胞的能力至关重要。此外，我们的初步数据表明，从TMZ诱导的淋巴细胞减少症中恢复过程中给予的疫苗会导致小鼠和人类中的体液反应显着增强和抗原特异性T细胞频率。尽管我们的初步数据使用带有转基因T细胞受体的小鼠的T细胞来评估在TMZ背景下疫苗和收养免疫疗法的组合，但这种方法不容易转化为人类研究。然而，以RNA形式（TTRNA）的肿瘤细胞总抗原含量的树突状细胞（DC）提供了一种创新的策略，我们和其他人已经安全，成功地为肿瘤特异性淋巴细胞扩展了针对广泛的肿瘤抗原的肿瘤特异性淋巴细胞。然后，我们的总体目标是在鼠类脑肿瘤模型中在鼠类脑肿瘤模型中从连续的淋巴结中恢复中，在从人类临床研究之前，在从连续的淋巴结中恢复中使用TTRNA疗法和TTRNA负载的直流疫苗。公共卫生相关性：对脑肿瘤的治疗代表了目前在美国提供的最昂贵的医疗疗法，而脑肿瘤仍然是儿童癌症死亡的最常见原因，并且在成人中造成的死亡人数比黑色素瘤更多。疫苗是对这些肿瘤治疗的一种有吸引力的辅助方法，但受到这些肿瘤的化学疗法的挫败，可杀死可能对这些疫苗反应的淋巴细胞。然而，化学疗法的这种作用实际上有助于维持化学疗法后立即注入的抗肿瘤淋巴细胞，因此我们将评估疫苗的综合疗效并在该提案中转移抗肿瘤淋巴细胞。