Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies
Anti-pancreatic tumor efficacy of a Listeria-based, Annexin A2-targeting immunotherapy in combination with anti-PD-1 antibodies
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DOI：
10.1186/s40425-019-0601-5
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发表时间：
2019-05-22
影响因子：
10.9
通讯作者：
Zheng, Lei
中科院分区：
文献类型：
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作者：
Kim, Victoria M.;Blair, Alex B.;Zheng, Lei
背景：免疫检查点抑制剂作为单一药物治疗胰腺导管腺癌（PDAC）无效。疫苗治疗可能使pdac对检查点抑制剂治疗敏感。膜联蛋白A2 （ANXA2）是一种促转移蛋白，先前被鉴定为一种相关的PDAC抗原，由分泌gm - csf的同种异体全胰腺肿瘤细胞疫苗（GVAX）表达，在PDAC患者中诱导抗ANXA2抗体反应。我们假设，以anxa2为靶点的疫苗方法不仅能引起免疫反应，还能产生抗肿瘤作用。方法：我们开发了一种基于李斯特菌的靶向anxa2的癌症免疫疗法（Lm-ANXA2），并在两种小鼠PDAC模型中研究其有效性。结果：Lm-ANXA2延长了小鼠pdac移植模型的存活时间。更重要的是，在给予抗pd -1抗体之前，在植入的PDAC模型中启动Lm-ANXA2治疗增加了治愈率，并在基因工程自发PDAC模型中导致客观肿瘤反应和延长生存期。在使用Lm-ANXA2和抗pd -1抗体治疗的肿瘤中，ANXA2特异性T细胞的INF表达显著增加。结论：李斯特菌疫苗免疫疗法首次被证明能够在“冷”肿瘤（如PDAC）的肿瘤微环境中诱导肿瘤抗原特异性T细胞反应，并使肿瘤对检查点抑制剂治疗敏感。此外，这种联合免疫疗法在自发发展的PDAC肿瘤小鼠中导致了客观的肿瘤反应和生存益处。因此，我们的研究支持将Lm-ANXA2与抗pd -1抗体联合用于PDAC治疗。
Background: Immune checkpoint inhibitors are not effective for pancreatic ductal adenocarcinoma (PDAC) as single agents. Vaccine therapy may sensitize PDACs to checkpoint inhibitor treatments. Annexin A2 (ANXA2) is a pro-metastasis protein, previously identified as a relevant PDAC antigen that is expressed by a GM-CSF-secreting allogenic whole pancreatic tumor cell vaccine (GVAX) to induce an anti-ANXA2 antibody response in patients with PDAC. We hypothesized that an ANXA2-targeting vaccine approach not only provokes an immune response but also mounts anti-tumor effects.Methods: We developed a Listeria-based, ANXA2-targeting cancer immunotherapy (Lm-ANXA2) and investigated its effectiveness within two murine models of PDAC.Results: We show that Lm-ANXA2 prolonged the survival in a transplant model of mouse PDACs. More importantly, priming with the Lm-ANXA2 treatment prior to administration of anti-PD-1 antibodies increased cure rates in the implanted PDAC model and resulted in objective tumor responses and prolonged survival in the genetically engineered spontaneous PDAC model. In tumors treated with Lm-ANXA2 followed by anti-PD-1 antibody, the T cells specific to ANXA2 had significantly increased INF expression.Conclusions: For the first time, a listeria vaccine-based immunotherapy was shown to be able to induce a tumor antigen-specific T cell response within the tumor microenvironment of a "cold" tumor such as PDAC and sensitize the tumor to checkpoint inhibitor therapy. Moreover, this combination immunotherapy led to objective tumor responses and survival benefit in the mice with spontaneously developed PDAC tumors. Therefore, our study supports developing Lm-ANXA2 as a therapeutic agent in combination with anti-PD-1 antibody for PDAC treatment.