通过对非人灵长类动物进行结构聚集的PD-L1抗原的主动免疫，打破了T和B免疫耐受，同时在免疫能力正常的小鼠肿瘤模型中显示出体内抗肿瘤效果。
Active immunization with a structurally aggregated PD-L1 antigen breaks T and B immune tolerance in non-human primates and exhibits in vivo anti-tumoral effects in immunocompetent mouse tumor models.
发表日期：2023 May 01
作者：
Y Morera-Díaz, C Canaán-Haden, J Sánchez-Ramírez, M Bequet-Romero, I Gonzalez-Moya, R Martínez, V Falcón, D Palenzuela, M Ayala-Ávila, J V Gavilondo
来源：
CANCER LETTERS
摘要：
尽管编程性死亡配体1（PD-L1）抑制疗法在癌症治疗中取得了临床上的成功，但只有一部分患者表现出持久的反应，因此需要进一步探索其他免疫疗法替代方案。本文报告了PKPD-L1Vac疫苗的开发，这是一种新的蛋白质疫苗候选者，使用磷酸铝作为佐剂，并将人类PD-L1的细胞外域与来自N.
meningitides（PKPD-L1）的LpdA蛋白47个氨基末端部分融合为抗原。PKPD-L1抗原具有与自然分子和其他PD-L1疫苗候选者不同的物理和生物学特征。这种二聚蛋白对PD-1和CD80受体的结合能力降低，可降低它们的促肿瘤活性。此外，PKPD-L1多肽的独特特征在结构上聚集可能是其免疫原性的可取之处。PKPD-L1Vac在小鼠和非人灵长类动物中引起了抗PD-L1特异性IgG抗体和T淋巴细胞介导的免疫。疫苗注射显示出在小鼠的CT-26和B16-F10原发肿瘤模型中的抗肿瘤活性。此外，PKPD-L1Vac接种增加了CT-26肿瘤组织中的肿瘤浸润淋巴细胞，并降低了CD3+CD8+PD1+高无反应性T细胞的比例，表明疫苗可能重塑肿瘤微环境。总之，PKPD-L1Vac疫苗展示了非常有前途的临床前结果，并应该进入I期临床试验。版权所有©2023 Elsevier B.V.。保留所有权利。
Despite the clinical success of the programmed death ligand 1 (PD-L1) blocking therapy in cancer treatment, only a subset of patients exhibits durable responses, therefore further exploration of other immunotherapeutic alternatives are needed. This paper reported the development of the PKPD-L1Vac vaccine, a new protein vaccine candidate that uses aluminum phosphate as an adjuvant and as an antigen the extracellular domain of human PD-L1 fused to a 47 amino-terminal portion of the LpdA protein from N. meningitides (PKPD-L1). The PKPD-L1 antigen has different physical and biological characteristics than those found in the natural molecule and in others PD-L1 vaccine candidates. The quimeric protein has a reduced binding capacity to the PD-1 and CD80 receptors to decrease their pro-tumoral activity. Besides, the distinctive feature of the PKPD-L1 polypeptide to be structurally aggregated could be desirable for its immunogenic properties. PKPD-L1Vac elicited anti-PD-L1-specific IgG antibodies and T lymphocyte-mediated immunity in mice and non-human primates. The vaccine administration demonstrated antitumor activity on CT-26 and B16-F10 primary tumor models in mice. Moreover, the immunization with PKPD-L1Vac increased the tumor-infiltrating lymphocytes and decreased the proportion of CD3+CD8+PD1+high anergic T cells in CT-26 tumor tissues, suggesting that the vaccine may remodel the tumor microenvironment. In summary, the PKPD-L1Vac vaccine exhibits very promising preclinical results and deserves to move forward to a phase I clinical trial.Copyright © 2023 Elsevier B.V. All rights reserved.