Glioblastoma radioimmunotherapy

胶质母细胞瘤放射免疫治疗

基本信息

批准号：
10057915
负责人：
KRISTOFFER Carl VALERIE
金额：
$ 23.29万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057915
关键词：
Address Adjuvant Adult Agonist Albumins Antigen Presentation Antigen-Presenting Cells Antigens Benchmarking Binding Biometry Blood - brain barrier anatomy Brain Neoplasms C57BL/6 Mouse Cells Clinic Clinical Combined Modality Therapy Complex Conformal Radiotherapy Foundations Glioblastoma Human Immune Immune Tolerance Immune response Immunity Immunization Immunosuppression Immunotherapy Infiltration Injections Lymphocyte Lymphoid Tissue MGMT gene Malignant - descriptor Malignant Neoplasms Modeling Molecular Mus Mutation Neoadjuvant Therapy O-(6)-methylguanine Operative Surgical Procedures Patients Peripheral Pilot Projects Primary Brain Neoplasms Radiation Radiation therapy Radio Radioimmunotherapy Relapse Research Personnel Rodent Safety Scheme Solid Subunit Vaccines Survival Rate T cell response T-Lymphocyte TLR9 gene Testing Time Tissues Toxic effect Toxicology Treatment Efficacy Tumor Antigens Tumor Immunity Vaccines base biomaterial compatibility chemoradiation chimeric antigen receptor T cells clinically translatable immune checkpoint blockade immunogenic immunogenicity immunoregulation improved in vivo lymph nodes mouse model nanocomplexes nanotechnology platform nanovaccine neoantigen vaccine neoantigens neoplastic cell neuro-oncology novel novel therapeutics pre-clinical preclinical study research clinical testing response standard of care temozolomide therapeutic vaccine therapy outcome treatment strategy tumor tumor heterogeneity tumor immunology tumor microenvironment tumor-immune system interactions vaccine candidate vaccine delivery vaccine immunotherapy vaccine response

项目摘要

Radioimmunotherapy for glioblastoma Abstract: Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor in adults. Current standard- of-care GBM treatment involving surgery and chemoradiation has very limited efficacy. Immunotherapy has been enthusiastically pursued for GBM treatment, but overall, GBM has thus far responded poorly to current immunotherapies, such as cancer therapeutic vaccines and immune checkpoint blockade (ICB). The underlying causes largely involve both local (in the tumor microenvironment) and systemic immunosuppression, heterogeneous and instable tumor cell subpopulations, and central immune tolerance against GBM-associated vaccines. Neoantigens, which are present solely in tumor cells but not in healthy cells, are attractive vaccine candidates due to their lack of central immune tolerance. Indeed, personalized neoantigen vaccines effectively treated some GBM patients. However, GBM generally has very low neoantigen loads, and the vast majority of neoantigens are poorly immunogenic, both of which hinder the wide clinic application of these vaccines. Combination therapy has enormous potential to address these challenges. Here, we propose to develop a novel radioimmunotherapy for GBM by combining fractionated conformal radiation, neoantigen nanovaccines, and ICB to promote the overall therapy response and prolong survival in a pre-clinical orthotopic GBM model. We will test this radioimmunotherapy in an orthotopic GBM model in syngeneic mice. First, fractionated conformal radiation could potently and precisely kill tumor cells and may also abolish local and systemic immunosuppression. Second, a GBM neoantigen nanovaccine will be developed to promote vaccine delivery into lymphoid tissues and antigen-presenting cells (APCs), thereby potentiating immunogenicity of the neoantigen and eliciting potent and durable GBM-specific T cell responses. Third, ICB can further promote anti-GBM immunity. To this end, we demonstrated before the potent therapeutic efficacy of fractionated conformal radiation in an orthotopic GBM mouse model. Moreover, we developed a platform of clinically promising nanovaccines that are formed in vivo from host albumin and albumin-binding vaccines (AlbiVax). AlbiVax are widely applicable and biocompatible. AlbiVax (1) delivered subunit vaccines to lymph nodes ~100-fold more efficiently than a clinic benchmark, (2) efficiently co-delivered molecular adjuvant and antigens to APCs, (3) enhanced antigen presentation, (4) elicited potent and durable antigen-specific immune responses, and (5) exerted great therapeutic efficacy either alone or together with ICB in multiple murine tumor models. Our albumin-binding moiety was validated in human to have efficient lymph node retention and an excellent safety profile. We have a team of investigators with complementary expertise for this study: Dr. Zhu for cancer nanovaccine and immunotherapy; Dr. Valerie for GBM radiotherapy; Dr. Bos for tumor immunology; Dr. Broaddus for clinical neuro-oncology; and Dr. Yan for preclinical/clinical biostatistics. Overall, we are confident to carry out rigorous pilot studies, and eventually establish this radioimmunotherapy strategy for clinical testing. Page 1

胶质母细胞瘤的放射免疫治疗抽象的：多形性胶质母细胞瘤（GBM）是成人中最常见和致命的原发性脑肿瘤。现行标准- 涉及手术和放化疗的非护理 GBM 治疗效果非常有限。免疫疗法已人们热衷于寻求 GBM 治疗，但总体而言，迄今为止，GBM 对目前的治疗效果不佳免疫疗法，例如癌症治疗疫苗和免疫检查点阻断（ICB）。底层的原因主要涉及局部（在肿瘤微环境中）和全身免疫抑制，异质性和不稳定的肿瘤细胞亚群，以及针对 GBM 相关的中枢免疫耐受疫苗。新抗原仅存在于肿瘤细胞中，而不存在于健康细胞中，是有吸引力的疫苗由于缺乏中枢免疫耐受而成为候选者。事实上，个性化新抗原疫苗可以有效地治疗了一些 GBM 患者。然而，GBM 通常具有非常低的新抗原负载，并且绝大多数新抗原的免疫原性较差，这都阻碍了这些疫苗的广泛临床应用。联合疗法具有应对这些挑战的巨大潜力。在这里，我们建议开发一部小说联合分段适形放射、新抗原纳米疫苗和 ICB 进行 GBM 放射免疫治疗促进临床前原位 GBM 模型的整体治疗反应并延长生存期。我们将测试这种放射免疫疗法在同基因小鼠的原位 GBM 模型中进行。一、分段共形辐射可以有效、精确地杀死肿瘤细胞，还可以消除局部和全身的免疫抑制。其次，将开发GBM新抗原纳米疫苗以促进疫苗递送至淋巴组织和抗原呈递细胞（APC），从而增强新抗原的免疫原性并引发强效和持久的 GBM 特异性 T 细胞反应。第三，ICB可以进一步促进抗GBM免疫。为此，我们之前已证明分次适形放射对原位 GBM 具有有效的治疗效果鼠标模型。此外，我们开发了一个在体内形成的具有临床前景的纳米疫苗平台来自宿主白蛋白和白蛋白结合疫苗 (AlbiVax)。 AlbiVax 具有广泛的适用性和生物相容性。 AlbiVax (1) 将亚单位疫苗递送至淋巴结的效率比临床基准高约 100 倍，(2) 有效地将分子佐剂和抗原共同递送至 APC，(3) 增强抗原呈递，(4) 引发有效且持久的抗原特异性免疫反应，并且（5）单独发挥巨大的治疗功效或与 ICB 一起用于多种小鼠肿瘤模型。我们的白蛋白结合部分在人体中得到验证具有有效的淋巴结保留和出色的安全性。我们有一个调查小组本研究的补充专业知识：朱博士在癌症纳米疫苗和免疫治疗方面的专业知识；瓦莱丽博士 GBM放射治疗； Bos博士负责肿瘤免疫学； Broaddus 博士负责临床神经肿瘤学；和颜博士临床前/临床生物统计学。总体而言，我们有信心进行严格的试点研究，并最终建立用于临床测试的放射免疫治疗策略。第1页