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GBM护理治疗具有非常有限的功效。免疫疗法一直是 积极追求GBM治疗，但总体而言，GBM迄今为止对目前的治疗反应不佳， 免疫疗法，如癌症治疗性疫苗和免疫检查点阻断（ICB）。底层 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性。事实上，个性化新抗原疫苗有效地 治疗了一些GBM患者。然而，GBM通常具有非常低的新抗原载量，并且绝大多数GBM的新抗原载量都非常低。 新抗原的免疫原性差，这两个问题阻碍了这些疫苗的广泛临床应用。 联合治疗具有解决这些挑战的巨大潜力。在这里，我们建议开发一种新的 联合分次适形放射、新抗原纳米疫苗和ICB治疗GBM的放射免疫疗法 以促进临床前原位GBM模型中的总体治疗反应并延长存活。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，分次适形放射 可以有效和精确地杀死肿瘤细胞，也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，以促进疫苗递送到淋巴组织中 和抗原呈递细胞（APC），从而增强新抗原的免疫原性并引发有效的免疫应答。 和持久的GBM特异性T细胞应答。第三，ICB可进一步促进抗GBM免疫。为此我们 在原位GBM中分次适形放射的有效治疗效果之前， 小鼠模型此外，我们还开发了一个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递送至APC，（3）增强抗原呈递，（4）诱导 有效和持久的抗原特异性免疫应答，以及（5）单独或单独使用 或与ICB一起用于多种鼠肿瘤模型。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极好的安全性。我们有一个调查小组 本研究的补充专业知识：Zhu博士负责癌症纳米疫苗和免疫治疗; Valerie博士 GBM放疗; Bos博士负责肿瘤免疫学;布罗德斯博士负责临床神经肿瘤学; Yan博士负责 临床前/临床生物统计学。总的来说，我们有信心进行严格的试点研究，并最终 建立这种放射免疫治疗策略用于临床测试。 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