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Polyomavirus-driven Merkel cell carcinoma: Prospects for therapeutic vaccine development.
Molecular Carcinogenesis ( IF 4.6 ) Pub Date : 2020-03-27 , DOI: 10.1002/mc.23190
Shira Tabachnick-Cherny 1 , Thomas Pulliam 1 , Candice Church 1 , David M Koelle 2, 3, 4, 5, 6 , Paul Nghiem 1, 7, 8
Affiliation  

Great strides have been made in cancer immunotherapy including the breakthrough successes of anti‐PD‐(L)1 checkpoint inhibitors. In Merkel cell carcinoma (MCC), a rare and aggressive skin cancer, PD‐(L)1 blockade is highly effective. Yet, ~50% of patients either do not respond to therapy or develop PD‐(L)1 refractory disease and, thus, do not experience long‐term benefit. For these patients, additional or combination therapies are needed to augment immune responses that target and eliminate cancer cells. Therapeutic vaccines targeting tumor‐associated antigens, mutated self‐antigens, or immunogenic viral oncoproteins are currently being developed to augment T‐cell responses. Approximately 80% of MCC cases in the United States are driven by the ongoing expression of viral T‐antigen (T‐Ag) oncoproteins from genomically integrated Merkel cell polyomavirus (MCPyV). Since T‐Ag elicits specific B‐ and T‐cell immune responses in most persons with virus‐positive MCC (VP‐MCC), and ongoing T‐Ag expression is required to drive VP‐MCC cell proliferation, therapeutic vaccination with T‐Ag is a rational potential component of immunotherapy. Failure of the endogenous T‐cell response to clear VP‐MCC (allowing clinically evident tumors to arise) implies that therapeutic vaccination will need to be potent anśd synergize with other mechanisms to enhance T‐cell activity against tumor cells. Here, we review the relevant underlying biology of VP‐MCC, potentially applicable therapeutic vaccine platforms, and antigen delivery formats. We also describe early successes in the field of therapeutic cancer vaccines and address several clinical scenarios in which VP‐MCC patients could potentially benefit from a therapeutic vaccine.

中文翻译:

多瘤病毒驱动的默克尔细胞癌:治疗性疫苗开发的前景。

癌症免疫治疗取得了长足的进步,包括抗PD-(L)1检查点抑制剂的突破性成功。在罕见的侵袭性皮肤癌默克尔细胞癌(MCC)中,PD-(L)1阻断非常有效。然而,约50%的患者对治疗无反应或发展为PD-(L)1难治性疾病,因此没有长期获益。对于这些患者,需要其他或联合疗法来增强靶向和消除癌细胞的免疫反应。目前正在开发针对肿瘤相关抗原,突变的自身抗原或免疫原性病毒癌蛋白的治疗性疫苗,以增强T细胞反应。在美国,大约80%的MCC病例是由基因组整合的默克尔细胞多瘤病毒(MCPyV)病毒T-抗原(T-Ag)癌蛋白的持续表达所驱动。由于T-Ag在大多数病毒阳性MCC(VP-MCC)患者中引起特定的B和T细胞免疫反应,并且需要持续的T-Ag表达来驱动VP-MCC细胞增殖,因此需要对T-Ag进行治疗性疫苗接种是免疫疗法的合理潜在成分。内源性T细胞对透明VP-MCC的反应失败(允许出现临床上明显的肿瘤),这意味着需要有效地治疗性疫苗接种并与其他机制协同作用,以增强T细胞对肿瘤细胞的活性。在这里,我们回顾了VP-MCC的相关基础生物学,可能适用的治疗性疫苗平台以及抗原递送形式。
更新日期:2020-03-27
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