Clinical Brain Tumor Development of a Cytomegalovirus-targeted Therapeutic with Vaccine pre-conditioning to Validate Novel Predictors of Vaccine Efficacy

通过疫苗预处理进行巨细胞病毒靶向治疗的临床脑肿瘤开发，以验证疫苗功效的新预测因子

• 批准号: 10310436
• 负责人: JOHN H. SAMPSON
• 金额: $ 40.1万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310436
• 关键词: Adjuvant; Antigens; Biological Assay; Blinded; Brain; Brain Neoplasms; CCL3 gene; Cancer Etiology; Cancer Vaccines; Cells; Clinical; Clinical Research; Cytomegalovirus; Data; Dendritic Cells; Development; Diphtheria; Diphtheria Toxoid; Dose; Enrollment; Environment; Excision; Genetic Markers; Glioblastoma; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Human; Immune response; Inactivated Vaccines; Infection; Integumentary system; Laboratories; Laboratory Study; Ligands; Measures; Messenger RNA; Methyltransferase; Mus; Nature; Newly Diagnosed; Nucleic Acids; Operative Surgical Procedures; Outcome; Patient-Focused Outcomes; Patients; Performance; Phase; Phosphoproteins; Physiologic pulse; Population; Prevention; Primary Brain Neoplasms; Production; Progression-Free Survivals; Prophylactic treatment; Proteins; Radiation; Radiation Dose Unit; Radiation therapy; Randomized; Regimen; Reporting; Sampling; Series; Site; T cell response; T-Lymphocyte; Tetanus; Vaccination; Vaccinee; Vaccines; Viral; Viral Antigens; Virus; Virus Latency; cell motility; chemotherapy; childhood cancer mortality; cohort; conditioning; conventional therapy; dendritic cell vaccination; draining lymph node; effective therapy; immunogenic; immunosuppressed; improved; latent infection; neoplasm immunotherapy; novel; phase II trial; phase III trial; preconditioning; predicting response; predictive marker; prevent; standard of care; survival prediction; targeted treatment; temozolomide; therapeutic vaccine; tumor; vaccine efficacy; young adult

ABSTRACT We have previously reported in Nature that patients with newly-diagnosed glioblastoma (GBM) randomized to receiving vaccines against Cytomegalovirus (CMV) using a potent vaccine site preconditioning regimen had a statistically significant increase in progression-free survival (PFS) and overall survival (OS). Half of the patients treated this way were still alive nearly 5 years later despite having no genetic markers predicting long-term survival. These results have been repeated in an additional cohort which showed a median survival of 44.1 months with ~36% of patients alive at 5 years. These results are remarkable because GBM remains uniformly lethal with a median OS of < 21 months despite surgical resection, high dose radiation therapy, chemotherapy, and tumor-treating fields, and only 10% of patients typically live past 5 years. In addition to demonstrating the potential for efficacy, our preliminary clinical and laboratory studies demonstrated that preconditioning the vaccination site with tetanus/diphtheria (Td) recall antigens increased DC migration to the draining lymph nodes (DLNs), which predicted PFS and OS as did the production of polyfunctional, CMV-specific T cells. These T cell responses were enhanced by GM-CSF at the vaccine site and pre-vaccination lymphodepletion with standard of care (SOC) temozolomide (TMZ), but inhibited by subsequent adjuvant doses of TMZ. Moreover, mechanistic studies in mice and humans revealed that efficacy was also dependent on producing high systemic levels of the chemokine (C-C motif) ligand 3 (CCL3). We believe these results warrant confirmation in a larger series of patients. Our Specific Aims are: 1. To conduct a larger Phase 2 trial of CMV pp65-loaded DC vaccination in patients with GBM. Patients with CMV positive, newly diagnosed GBM will receive serial vaccines with CMV pp65-loaded DCs with GM-CSF and Td vaccine site preconditioning. GM-CSF and Td vaccine site preconditioning will be employed because they have been shown to enhance DC migration and increase polyfunctional T cell responses in prior studies. TMZ will be given prior to vaccination to induce homeostatic proliferation of the vaccine-induced T cell responses but not given subsequently to prevent killing of vaccine-induced T cells. 2. To confirm predictors of survival. In our prior studies DC migration to draining lymph nodes, systemic and local CCL3, and CMV pp65-specific polyfunctional T cells predicted PFS and OS. Here we will collect samples to confirm these predictors.

摘要 我们之前在《自然》杂志上报道过，新诊断的胶质母细胞瘤（GBM）患者被随机分配到 使用有效的疫苗部位预处理方案接种巨细胞病毒（CMV）疫苗， 无进展生存期（PFS）和总生存期（OS）的统计学显著增加。一半的患者 尽管没有遗传标记预测长期存活， 生存这些结果在另一个队列中重复，显示中位生存期为44.1 3个月，约36%的患者在5年时存活。这些结果是显著的，因为GBM保持均匀 尽管进行了手术切除、高剂量放疗、化疗， 和肿瘤治疗领域，只有10%的患者通常活超过5年。 除了证明疗效的潜力，我们的初步临床和实验室研究 表明用破伤风/白喉（Td）回忆抗原预处理疫苗接种部位可增加DC 向引流淋巴结（DLN）的迁移，其预测PFS和OS， 多功能CMV特异性T细胞。这些T细胞应答在疫苗部位被GM-CSF增强， 用标准治疗（SOC）替莫唑胺（TMZ）进行接种前淋巴细胞耗竭，但随后的 TMZ的辅助剂量。此外，对小鼠和人类的机制研究表明， 依赖于产生高系统水平的趋化因子（C-C基序）配体3（CCL 3）。 我们认为这些结果需要在更大范围的患者中得到证实。 我们的具体目标是： 1.在GBM患者中进行CMV pp 65负载DC疫苗接种的更大规模2期试验。患者 对于CMV阳性，新诊断的GBM将接受含有GM-CSF的CMVpp 65负载的DC的系列疫苗 和Td疫苗位点预处理。将采用GM-CSF和Td疫苗部位预处理，因为 在先前的研究中，它们已经显示出增强DC迁移和增加多功能T细胞应答。 TMZ将在疫苗接种前给予，以诱导疫苗诱导的T细胞应答的稳态增殖 但随后不给予以防止杀死疫苗诱导的T细胞。 2.以确定生存的预测因素。在我们先前的研究中，DC迁移到引流淋巴结，全身和全身淋巴结， 局部CCL 3和CMV pp 65特异性多功能T细胞预测PFS和OS。 来证实这些预测。

项目成果

A conjoined universal helper epitope can unveil antitumor effects of a neoantigen vaccine targeting an MHC class I-restricted neoepitope.

• DOI: 10.1038/s41541-020-00273-5
• 发表时间: 2021-01-18
• 期刊: NPJ vaccines
• 影响因子: 9.2
• 作者: Swartz AM;Congdon KL;Nair SK;Li QJ;Herndon JE 2nd;Suryadevara CM;Riccione KA;Archer GE;Norberg PK;Sanchez-Perez LA;Sampson JH
• 通讯作者: Sampson JH

Antibody, T-cell and dendritic cell immunotherapy for malignant brain tumors.

• DOI: 10.2217/fon.13.47
• 发表时间: 2013-07
• 期刊: Future oncology (London, England)
• 作者: Chandramohan V;Mitchell DA;Johnson LA;Sampson JH;Bigner DD
• 通讯作者: Bigner DD

Combating immunosuppression in glioma.

• DOI: 10.2217/14796694.4.3.433
• 发表时间: 2008-06
• 期刊: Future oncology
• 影响因子: 3.3
• 作者: E. A. Vega;M. Graner;J. Sampson

Toward effective immunotherapy for the treatment of malignant brain tumors.

• DOI: 10.1016/j.nurt.2009.04.003
• 发表时间: 2009-07
• 期刊: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
• 作者: Mitchell DA;Sampson JH
• 通讯作者: Sampson JH

Clinical applications of a peptide-based vaccine for glioblastoma.

胶质母细胞瘤肽疫苗的临床应用。

• DOI: 10.1016/j.nec.2009.09.001
• 发表时间: 2010
• 期刊: Neurosurgery clinics of North America
• 影响因子: 2.6
• 作者: Kanaly,CharlesW;Ding,Dale;Heimberger,AmyB;Sampson,JohnH
• 通讯作者: Sampson,JohnH