Glioblastoma radioimmunotherapy

胶质母细胞瘤的放射免疫治疗 摘要： 多形性胶质母细胞瘤(GBM)是成人最常见、最致命的原发脑肿瘤。现行标准- 包括手术和放化疗在内的OCARE-CARE-GBM治疗效果非常有限。免疫疗法一直是 热衷于GBM治疗，但总体而言，GBM迄今对当前的反应不佳 免疫疗法，如癌症治疗性疫苗和免疫检查点阻断(ICB)。潜在的 病因主要涉及局部(在肿瘤微环境中)和全身免疫抑制， 异质性和不稳定性肿瘤细胞亚群与中枢免疫耐受 疫苗。新抗原只存在于肿瘤细胞中，而不存在于健康细胞中，是有吸引力的疫苗。 候选人由于缺乏中枢免疫耐受性。事实上，个性化的新抗原疫苗有效地 治疗了一些GBM患者。然而，GBM通常具有非常低的新抗原负荷，并且绝大多数 新抗原的免疫原性较差，这两种情况都阻碍了疫苗的广泛临床应用。 联合疗法在应对这些挑战方面具有巨大的潜力。在这里，我们建议开发一部小说 分次适形放射、新抗原纳米疫苗和ICB联合放射免疫治疗基底膜 目的：在临床前原位肾小球基底膜模型中促进整体治疗反应和延长生存期。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。第一，分次共形辐射 可以有效而准确地杀死肿瘤细胞，还可能取消局部和全身免疫抑制。 其次，将开发一种GBM新抗原纳米疫苗，以促进疫苗进入淋巴组织 和抗原提呈细胞(APC)，从而增强新抗原的免疫原性并激发效力 和持久的GBM特异性T细胞反应。第三，ICB可进一步促进抗GBM免疫。为此，我们 分次适形放疗对原位肾小球基底膜的有效治疗效果 老鼠模型。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)将亚单位疫苗输送到淋巴结的效率是临床基准的100倍左右，(2) 有效地将分子佐剂和抗原共同递送到APC，(3)增强抗原提呈，(4)诱导 有效和持久的抗原特异性免疫反应，以及(5)单独发挥巨大的治疗效果 或与ICB联合应用于多种小鼠肿瘤模型。我们的白蛋白结合部分在人类中得到了验证 具有高效的淋巴滞留和极佳的安全性。我们有一组调查人员 这项研究的互补专业知识：朱博士用于癌症纳米疫苗和免疫疗法；Valerie博士用于 GBM放射治疗；博斯医生肿瘤免疫学；布罗德杜斯医生临床神经肿瘤学；严医生 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 建立这一放射免疫治疗策略，用于临床试验。 第1页

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