Department of Pharmaceutics and Center for Pharmaceutical Engineering and Sciences; The Developmental Therapeutics Program, Massey Cancer Center; Virginia Commonwealth University, Richmond, VA 23298, USA.
Department of Pharmaceutical Sciences, College of Pharmacy; Biointerfaces Institute. University of Michigan, Ann Arbor, MI 48109, USA.
Theranostics. 2023 Aug 6;13(13):4304-4315. doi: 10.7150/thno.84443. eCollection 2023.
Glioblastoma multiforme (GBM) is the most common and lethal type of adult brain cancer. Current GBM standard of care, including radiotherapy, often ends up with cancer recurrence, resulting in limited long-term survival benefits for GBM patients. Immunotherapy, such as immune checkpoint blockade (ICB), has thus far shown limited clinical benefit for GBM patients. Therapeutic vaccines hold great potential to elicit anti-cancer adaptive immunity, which can be synergistically combined with ICB and radiotherapy. Peptide vaccines are attractive for their ease of manufacturing and stability, but their therapeutic efficacy has been limited due to poor vaccine co-delivery and the limited ability of monovalent antigen vaccines to prevent tumor immune evasion. To address these challenges, here, we report GBM radioimmunotherapy that combines radiotherapy, ICB, and multivalent lymph-node-targeting adjuvant/antigen-codelivering albumin-binding vaccines (AAco-AlbiVax). Specifically, to codeliver peptide neoantigens and adjuvant CpG to lymph nodes (LNs), we developed AAco-AlbiVax based on a Y-shaped DNA scaffold that was site-specifically conjugated with CpG, peptide neoantigens, and albumin-binding maleimide-modified Evans blue derivative (MEB). As a result, these vaccines elicited antitumor immunity including neoantigen-specific CD8 T cell responses in mice. In orthotopic GBM mice, the combination of AAco-AlbiVax, ICB, and fractionated radiation enhanced GBM therapeutic efficacy. However, radioimmunotherapy only trended more efficacious over radiotherapy alone. Taken together, these studies underscore the great potential of radioimmunotherapy for GBM, and future optimization of treatment dosing and scheduling would improve the therapeutic efficacy.
多形性胶质母细胞瘤(GBM)是最常见和致命的成人脑癌。目前的 GBM 标准治疗方法,包括放疗,往往最终导致癌症复发,导致 GBM 患者的长期生存获益有限。免疫疗法,如免疫检查点阻断(ICB),迄今为止对 GBM 患者的临床获益有限。治疗性疫苗具有引发抗癌适应性免疫的巨大潜力,可以与 ICB 和放疗协同结合。肽疫苗因其易于制造和稳定性而具有吸引力,但由于疫苗共递送和单价抗原疫苗预防肿瘤免疫逃逸的能力有限,其治疗效果受到限制。为了解决这些挑战,我们在这里报告了一种将放疗、ICB 和多价淋巴结靶向佐剂/抗原递呈白蛋白结合疫苗(AAco-AlbiVax)结合的 GBM 放射免疫治疗。具体来说,为了将肽新抗原和佐剂 CpG 共递送至淋巴结(LN),我们基于一种 Y 形 DNA 支架开发了 AAco-AlbiVax,该支架通过定点与 CpG、肽新抗原和白蛋白结合的马来酰亚胺修饰 Evans 蓝衍生物(MEB)进行共轭。结果,这些疫苗在小鼠中引发了抗肿瘤免疫,包括新抗原特异性 CD8 T 细胞反应。在原位 GBM 小鼠中,AAco-AlbiVax、ICB 和分割放疗的联合增强了 GBM 的治疗效果。然而,放射免疫治疗仅比单独放疗更有效。总之,这些研究强调了放射免疫治疗对 GBM 的巨大潜力,未来优化治疗剂量和方案将提高治疗效果。
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