背景:尽管在成功使用免疫治疗治疗多种实体瘤方面取得了进展,在治疗脑肿瘤方面的应用已经相当滞后。这是由于,至少在某种程度上,脑肿瘤中缺乏可介导肿瘤排斥反应的特征明确的抗原;这些肿瘤的低突变负担限制了可靶向新抗原的丰度;以及阻碍产生持续和生产性免疫反应的免疫学“冷”肿瘤微环境。在COVID-19mRNA疫苗获得普遍批准后,基于mRNA的治疗领域经历了一个福音。基于mRNA的免疫治疗剂也因其彻底改变癌症治疗的潜力而引起了广泛的兴趣。在这项研究中,我们开发了一种新颖且可扩展的方法,用于生产个性化的基于mRNA的疗法,该疗法在单一疗法中靶向多种肿瘤排斥抗原,用于治疗难治性脑肿瘤.
方法:使用我们称为开放阅读框架抗原网络(O.R.A.N)的癌症免疫基因组学管道,鉴定胶质母细胞瘤和髓母细胞瘤肿瘤的肿瘤特异性新抗原和异常过度表达的肿瘤相关抗原。使用选择性基因捕获和富集策略为每个单独的肿瘤模型开发了个性化的肿瘤抗原特异性mRNA疫苗。在高度侵袭性的鼠GBM模型中,与抗PD-1免疫检查点阻断疗法或使用离体扩增的肿瘤抗原特异性淋巴细胞的过继细胞疗法组合评估个性化mRNA疫苗的免疫原性和功效。
结果:我们的结果证明了抗原特异性mRNA疫苗在GBM宿主中引发强大的抗肿瘤免疫应答的有效性。我们的发现证实了以效应子功能增强为特征的肿瘤浸润淋巴细胞的增加,肿瘤内和全身,在抗原特异性mRNA定向免疫治疗后,导致肿瘤微环境从免疫冷到热的有利转变。还证明了产生靶向人GBM抗原的个性化mRNA疫苗的能力。
结论:我们已经建立了一种个性化和可定制的mRNA治疗方法,该方法有效地靶向多种肿瘤抗原,并在临床前脑肿瘤模型中显示出有效的抗肿瘤反应。这种平台mRNA技术独特地解决了肿瘤异质性和低抗原负担的挑战,靶向经典免疫疗法抗性中枢神经系统恶性肿瘤的两个关键缺陷,可能还有其他类型的冷肿瘤.
Despite advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized antigens expressed within brain tumors that can mediate tumor rejection; the low mutational burden of these tumors that limits the abundance of targetable neoantigens; and the immunologically \"cold\" tumor microenvironment that hampers the generation of sustained and productive immunologic responses. The field of mRNA-based therapeutics has experienced a boon following the universal approval of COVID-19 mRNA vaccines. mRNA-based immunotherapeutics have also garnered widespread interest for their potential to revolutionize cancer treatment. In this study, we developed a novel and scalable approach for the production of personalized mRNA-based therapeutics that target multiple tumor rejection antigens in a single therapy for the treatment of refractory brain tumors.
Tumor-specific neoantigens and aberrantly overexpressed tumor-associated antigens were identified for glioblastoma and medulloblastoma tumors using our cancer immunogenomics pipeline called Open Reading Frame Antigen Network (O.R.A.N). Personalized tumor antigen-specific mRNA vaccine was developed for each individual tumor model using selective gene capture and enrichment strategy. The immunogenicity and efficacy of the personalized mRNA vaccines was evaluated in combination with anti-PD-1 immune checkpoint blockade therapy or adoptive cellular therapy with ex vivo expanded tumor antigen-specific lymphocytes in highly aggressive murine GBM models.
Our results demonstrate the effectiveness of the antigen-specific mRNA vaccines in eliciting robust anti-tumor immune responses in GBM hosts. Our findings substantiate an increase in tumor-infiltrating lymphocytes characterized by enhanced effector function, both intratumorally and systemically, after antigen-specific mRNA-directed immunotherapy, resulting in a favorable shift in the tumor microenvironment from immunologically cold to hot. Capacity to generate personalized mRNA vaccines targeting human GBM antigens was also demonstrated.
We have established a personalized and customizable mRNA-therapeutic approach that effectively targets a plurality of tumor antigens and demonstrated potent anti-tumor response in preclinical brain tumor models. This platform mRNA technology uniquely addresses the challenge of tumor heterogeneity and low antigen burden, two key deficiencies in targeting the classically immunotherapy-resistant CNS malignancies, and possibly other cold tumor types.