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.

抽象的 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 使用有效的疫苗位点预处理方案接种巨细胞病毒 (CMV) 疫苗有 无进展生存期（PFS）和总生存期（OS）具有统计学意义的显着增加。一半的病人 尽管没有预测长期生存的遗传标记，但以这种方式治疗的人在近 5 年后仍然活着 生存。这些结果在另一个队列中得到重复，显示中位生存率为 44.1 约 36% 的患者在 5 岁时仍存活数月。这些结果是显着的，因为 GBM 保持一致 尽管进行了手术切除、高剂量放射治疗、化疗、 和肿瘤治疗领域，只有 10% 的患者通常能活过 5 年。 除了证明功效潜力外，我们的初步临床和实验室研究 证明用破伤风/白喉 (Td) 记忆抗原预处理疫苗接种部位可增加 DC 迁移至引流淋巴结 (DLN)，这可预测 PFS 和 OS，就像产生 多功能、CMV 特异性 T 细胞。这些 T 细胞反应被疫苗部位的 GM-CSF 增强，并且 疫苗接种前使用标准护理 (SOC) 替莫唑胺 (TMZ) 进行淋巴细胞清除，但随后会受到抑制 TMZ 的辅助剂量。此外，对小鼠和人类的机制研究表明，功效也 依赖于产生高全身水平的趋化因子（C-C 基序）配体 3 (CCL3)。 我们相信这些结果值得在更大范围的患者中得到证实。 我们的具体目标是： 1. 在 GBM 患者中进行更大规模的 CMV pp65 负载 DC 疫苗接种 2 期试验。患者 CMV 呈阳性的新诊断 GBM 将接受含有 CMV pp65 负载的 DC 和 GM-CSF 的系列疫苗 和 Td 疫苗位点预处理。将采用 GM-CSF 和 Td 疫苗位点预处理，因为 在之前的研究中，它们已被证明可以增强 DC 迁移并增加多功能 T 细胞反应。 TMZ 将在疫苗接种前给予，以诱导疫苗诱导的 T 细胞反应的稳态增殖 但随后不给予以防止疫苗诱导的 T 细胞被杀死。 2. 确认生存预测因子。在我们之前的研究中，DC 迁移至引流淋巴结、全身和 局部 CCL3 和 CMV pp65 特异性多功能 T 细胞预测 PFS 和 OS。我们将在这里收集样本 来确认这些预测。

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

Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells.

• DOI: 10.1158/1078-0432.ccr-13-3268
• 发表时间: 2014-05-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Nair SK;De Leon G;Boczkowski D;Schmittling R;Xie W;Staats J;Liu R;Johnson LA;Weinhold K;Archer GE;Sampson JH;Mitchell DA
• 通讯作者: Mitchell DA