CCL3 as a Developmental Therapeutic to Enhance Brain Tumor Therapy

CCL3 作为一种增强脑肿瘤治疗的发育疗法

基本信息

批准号：
10055778
负责人：
JOHN H. SAMPSON
金额：
$ 34.78万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10055778
关键词：
Adjuvant Affect Antigens Bilateral Brain Brain Neoplasms CCL3 gene CCR1 gene CCR5 gene CD8-Positive T-Lymphocytes Cancer Etiology Cells Cervical Cessation of life Clinical Trials Cytotoxic T-Lymphocytes Data Dendritic Cell Vaccine Dendritic Cells Developmental Therapeutics Program Diphtheria Toxoid Dose Glioblastoma Glioma Goals Human Immune Immunity Immunotherapy Individual Inflammation Inflammatory Interferon Type II Intracranial Neoplasms Laboratories Ligands Malignant - descriptor Malignant neoplasm of brain Mediator of activation protein Memory Methods Modeling Mus Nature Newly Diagnosed Normal tissue morphology Patients Pharmaceutical Preparations Primary Brain Neoplasms Production Progression-Free Survivals Publications Publishing Renal carcinoma Role Signal Transduction Site Source T cell response T-Lymphocyte TNF gene Tetanus Toxic effect Tumor Antigens Tumor Immunity Vaccination Vaccines Work antigen-specific T cells cell motility chemokine childhood cancer mortality cytokine dendritic cell vaccination draining lymph node early phase clinical trial effector T cell gamma-Chemokines immune function improved individual patient innovation lymph nodes melanoma migration mouse model novel patient response pre-clinical preclinical study preconditioning receptor response targeted treatment trafficking tumor tumor growth vaccine delivery vaccine development vaccine efficacy young adult

项目摘要

ABSTRACT: Malignant primary brain tumors represent the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Glioblastoma (GBM) is uniformly lethal, and current therapy is non-specific and produces a median overall survival of <15 months. In contrast, immunotherapy promises an exquisitely precise approach, and substantial evidence suggests that T cells can eradicate large, well-established tumors in mice and humans even when tumors reside within the brain. Dendritic cells (DCs) bearing tumor antigen can be delivered as a vaccine and migrate to the draining lymph nodes (DLN) to trigger the formation of potent tumor-specific cytotoxic T lymphocytes (CTLs) capable of eradicating tumor while leaving normal tissue unharmed. However, despite individual cases of remarkable patient responses to antitumor DC vaccination, overall objective responses in early phase clinical trials have remained under 15%. The migration of vaccine-delivered DCs is low (~5%), and preclinical studies have demonstrated that preconditioning the vaccine site with the inflammatory cytokines can increase DC migration to the DLN and proportionately increase the magnitude of the antigen-specific T cell response. We hypothesized that preconditioning the vaccine site with the recall antigens in Tetanus/diphtheria toxoid (Td) would induce inflammation, increase DC migration, and elicit more consistently efficacious antitumor immunity. In a recent study in patients with newly diagnosed GBM published in Nature, we demonstrated that unilaterally preconditioning one vaccine site with Td resulted in increased bilateral DC migration to the DLNs and a significant increase in progression free survival and OS - with three of the six Td treated patients living past 4.5 years. A recapitulative murine model corroborated these findings, demonstrating that Td preconditioning both enhanced systemic DC migration to the DLNs and suppressed tumor growth in an antigen-dependent manner. Examination of both patient and murine sera revealed that the chemokine (C-C motif) ligand 3 (CCL3) was the only cytokine or chemokine significantly upregulated after Td preconditioning. Furthermore, in mice we demonstrated that the systemic increase in DC migration after Td preconditioning is dependent upon CD4+ memory effector T cells (CD4Td−mem) and CCL3. However, recent pilot data from our laboratory indicate that the CD4Td−mem are actually responsible for the production of CCL3, suggesting CCL3 serves as the primary driver of the improved antigen-dependent immunity from Td preconditioning. We hypothesize that in addition to enhancing the migration of DCs to the DLN, that CCL3 directly increases antigen-specific T cell magnitude and functionality as well as immune cell trafficking to tumor. This proposal will mechanistically determine the specific role of CCL3 in DC migration, antigen-specific T cell responses, as well as immune cell trafficking, and will further assess if the antitumor efficacy of DC vaccination can be further enhanced by the use of exogenous CCL3 as a vaccine-enhancing drug.

摘要：恶性原发性脑肿瘤是儿童癌症死亡最常见的原因和年轻人比肾脏或黑色素瘤癌的死亡人数更多。胶质母细胞瘤（GBM）为统一的致命，当前的治疗是非特异性的，并且总体生存期的中位数<15个月。在对比，免疫疗法有望准确的方法，大量证据表明细胞也可以在小鼠和人类中播放大型肿瘤，即使肿瘤居住在脑。轴承肿瘤抗原的树突状细胞（DC）可以作为真空递送并迁移到排水淋巴结（DLN）触发能够形成有效的肿瘤特异性细胞毒性T淋巴细胞（CTL）消除肿瘤，同时使正常组织不受伤害。但是，要造成非凡的案例患者对抗肿瘤直流疫苗接种的反应，早期临床试验中的总体客观反应具有保持在15％以下。疫苗传递的DC的迁移较低（〜5％），临床前研究的迁移证明用炎症细胞因子预处理疫苗部位可以增加直流迁移 DLN并按比例增加了抗原特异性T细胞反应的大小。我们假设用破伤风/白喉毒素（TD）中的回忆抗原对疫苗部位进行预处理会引起炎症，增加直流迁移，并引起更有效的抗肿瘤免疫组织化学。在最近针对自然界发表的新诊断为GBM的患者的一项研究中，我们证明了单方面用TD将一个疫苗部位的预处理导致双侧直流向DLN迁移，并增加无进展生存和OS的显着增加 - 六名TD治疗的患者中有三名居住于4.5 年。概括的鼠模型证实了这些发现，证明了TD对两者的预处理增强了全身性直流向DLN迁移，并以抗原依赖性方式抑制了肿瘤的生长。对患者和鼠血清的检查表明，趋化因子（C-C基序）配体3（CCL3）是在TD预处理后，只有细胞因子或趋化因子会显着更新。此外，在小鼠中证明TD预处理后直流迁移的系统性增加取决于CD4+ 记忆效应T细胞（CD4TD -MEM）和CCL3。但是，我们实验室指标的最新试点数据是 CD4TD-MEM实际上负责CCL3的生产，这表明CCL3用作主要驱动程序改善了抗原依赖性免疫的TD预处理。我们假设这是加强DC向DLN的迁移，CCL3直接增加了抗原特异性T细胞幅度和功能以及免疫核管对肿瘤的运输。该建议将机械化确定 CCL3在DC迁移，抗原特异性T细胞反应以及免疫核管贩运以及将进一步评估DC疫苗接种的抗肿瘤效率是否可以通过使用外源性进一步提高 CCL3作为增强疫苗的药物。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Checkpoint inhibitor immunotherapy for glioblastoma: current progress, challenges and future outlook.

DOI：
10.1080/17512433.2020.1817737
发表时间：
2020-10
期刊：
Expert review of clinical pharmacology
影响因子：
4.4
作者：
Gedeon PC;Champion CD;Rhodin KE;Woroniecka K;Kemeny HR;Bramall AN;Bernstock JD;Choi BD;Sampson JH
通讯作者：
Sampson JH

Advances and challenges: dendritic cell vaccination strategies for glioblastoma.

DOI：
10.1080/14760584.2016.1218762
发表时间：
2017-01
期刊：
Expert review of vaccines
影响因子：
6.2
作者：
Schaller TH;Sampson JH
通讯作者：
Sampson JH

A Rationally Designed Fully Human EGFRvIII:CD3-Targeted Bispecific Antibody Redirects Human T Cells to Treat Patient-derived Intracerebral Malignant Glioma.

DOI：
10.1158/1078-0432.ccr-17-0126
发表时间：
2018-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Gedeon PC;Schaller TH;Chitneni SK;Choi BD;Kuan CT;Suryadevara CM;Snyder DJ;Schmittling RJ;Szafranski SE;Cui X;Healy PN;Herndon JE 2nd;McLendon RE;Keir ST;Archer GE;Reap EA;Sanchez-Perez L;Bigner DD;Sampson JH
通讯作者：
Sampson JH

Enhancing T Cell Chemotaxis and Infiltration in Glioblastoma.