Cancer-specific mutations can lead to peptides of unique sequence presented on MHC class I to CD8 T cells. These neoantigens can be potent tumour-rejection antigens, appear to be the driving force behind responsiveness to anti-CTLA-4 and anti-PD1/L1-based therapies and have been used to develop personalized vaccines. The platform for delivering neoantigen-based vaccines has varied, and further optimization of both platform and adjuvant will be necessary to achieve scalable vaccine products that are therapeutically effective at a reasonable cost. Here, we developed a platform for testing potential CD8 T cell tumour vaccine candidates. We used a high-affinity alpaca-derived VHH against MHC class II to deliver peptides to professional antigen-presenting cells. We show in vitro and in vivo that peptides derived from the model antigen ovalbumin are better able to activate naive ovalbumin-specific CD8 T cells when conjugated to an MHC class II-specific VHH when compared with an irrelevant control VHH. We then used the VHH-peptide platform to evaluate a panel of candidate neoantigens in vivo in a mouse model of pancreatic cancer. None of the candidate neoantigens tested led to protection from tumour challenge; however, we were able to show vaccine-induced CD8 T cell responses to a melanoma self-antigen that was augmented by combination therapy with the synthetic cytokine mimetic Neo2/15.

中文翻译：

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Neoleukin-2 增强抗 MHC II 类 VHH 靶向肽疫苗接种下游的抗肿瘤免疫力。

癌症特异性突变可导致在 MHC I 类至 CD8 T 细胞上呈递独特序列的肽。这些新抗原可能是有效的肿瘤排斥抗原，似乎是对抗 CTLA-4 和抗 PD1/L1 疗法产生反应的驱动力，并已用于开发个性化疫苗。提供基于新抗原的疫苗的平台多种多样，需要进一步优化平台和佐剂，以实现以合理成本获得治疗效果的可扩展疫苗产品。在这里，我们开发了一个平台来测试潜在的 CD8 T 细胞肿瘤疫苗候选者。我们使用抗 MHC II 类的高亲和力羊驼毛衍生 VHH 将肽递送至专业抗原呈递细胞。我们在体外和体内表明，与不相关的对照 VHH 相比，当与 MHC II 类特异性 VHH 偶联时，源自模型抗原卵清蛋白的肽能够更好地激活幼稚卵清蛋白特异性 CD8 T 细胞。然后，我们使用 VHH 肽平台在胰腺癌小鼠模型中体内评估一组候选新抗原。测试的候选新抗原都没有导致对肿瘤攻击的保护；然而，我们能够显示疫苗诱导的 CD8 T 细胞对黑色素瘤自身抗原的反应，该抗原通过与合成细胞因子模拟物 Neo2/15 的联合治疗增强。然后，我们使用 VHH 肽平台在胰腺癌小鼠模型中体内评估一组候选新抗原。测试的候选新抗原都没有导致对肿瘤攻击的保护；然而，我们能够显示疫苗诱导的 CD8 T 细胞对黑色素瘤自身抗原的反应，该抗原通过与合成细胞因子模拟物 Neo2/15 的联合治疗增强。然后，我们使用 VHH 肽平台在胰腺癌小鼠模型中体内评估一组候选新抗原。测试的候选新抗原都没有导致对肿瘤攻击的保护；然而，我们能够显示疫苗诱导的 CD8 T 细胞对黑色素瘤自身抗原的反应，该抗原通过与合成细胞因子模拟物 Neo2/15 的联合治疗增强。