Desai Rupen, Suryadevara Carter M, Batich Kristen A, Farber S Harrison, Sanchez-Perez Luis, Sampson John H
a Duke Brain Tumor Immunotherapy Program, Department of Neurosurgery , Duke University Medical Center , Durham , NC , USA.
b The Preston Robert Tisch Brain Tumor Center , Duke University Medical Center , Durham , NC , USA.
Expert Opin Emerg Drugs. 2016 Jun;21(2):133-45. doi: 10.1080/14728214.2016.1186643.
Immunotherapy for brain cancer has evolved dramatically over the past decade, owed in part to our improved understanding of how the immune system interacts with tumors residing within the central nervous system (CNS). Glioblastoma (GBM), the most common primary malignant brain tumor in adults, carries a poor prognosis (<15 months) and only few advances have been made since the FDA's approval of temozolomide (TMZ) in 2005. Importantly, several immunotherapies have now entered patient trials based on promising preclinical data, and recent studies have shed light on how GBM employs a slew of immunosuppressive mechanisms that may be targeted for therapeutic gain. Altogether, accumulating evidence suggests immunotherapy may soon earn its keep as a mainstay of clinical management for GBM.
Here, we review cancer vaccines, checkpoint inhibitors, adoptive T-cell immunotherapy, and oncolytic virotherapy.
Checkpoint blockade induces antitumor activity by preventing negative regulation of T-cell activation. This platform, however, depends on an existing frequency of tumor-reactive T cells. GBM tumors are exceptionally equipped to prevent this, occupying low levels of antigen expression and elaborate mechanisms of immunosuppression. Therefore, checkpoint blockade may be most effective when used in combination with a DC vaccine or adoptively transferred tumor-specific T cells generated ex vivo. Both approaches have been shown to induce endogenous immune responses against tumor antigens, providing a rationale for use with checkpoint blockade where both primary and secondary responses may be potentiated.
在过去十年中，脑癌免疫疗法取得了巨大进展，部分原因是我们对免疫系统与中枢神经系统（CNS）内肿瘤相互作用的理解有所提高。胶质母细胞瘤（GBM）是成人中最常见的原发性恶性脑肿瘤，预后较差（<15个月），自2005年美国食品药品监督管理局（FDA）批准替莫唑胺（TMZ）以来，进展甚微。重要的是，基于有前景的临床前数据，几种免疫疗法现已进入患者试验阶段，最近的研究揭示了GBM如何采用一系列免疫抑制机制，这些机制可能成为治疗靶点以实现治疗效果。总体而言，越来越多的证据表明免疫疗法可能很快成为GBM临床管理的主要手段。
在此，我们综述癌症疫苗、检查点抑制剂、过继性T细胞免疫疗法和溶瘤病毒疗法。
检查点阻断通过阻止T细胞活化的负调节来诱导抗肿瘤活性。然而，该平台依赖于现有的肿瘤反应性T细胞频率。GBM肿瘤特别擅长防止这种情况发生，其抗原表达水平较低且具有复杂的免疫抑制机制。因此，检查点阻断与DC疫苗或体外产生的过继性转移肿瘤特异性T细胞联合使用时可能最有效。这两种方法均已显示可诱导针对肿瘤抗原的内源性免疫反应，为与检查点阻断联合使用提供了理论依据，因为在这种联合使用中，原发性和继发性反应可能都会得到增强。
