Leukemia vaccine overcomes limitations of checkpoint blockade by evoking clonal T cell responses in a murine acute myeloid leukemia model.
Leukemia vaccine overcomes limitations of checkpoint blockade by evoking clonal T cell responses in a murine acute myeloid leukemia model.
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DOI：
10.3324/haematol.2020.259457
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发表时间：
2021-05-01
期刊：
影响因子：
10.1
通讯作者：
Avigan D
中科院分区：
文献类型：
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作者：
Stroopinsky D;Liegel J;Bhasin M;Cheloni G;Thomas B;Bhasin S;Panchal R;Ghiasuddin H;Rahimian M;Nahas M;Orr S;Capelletti M;Torres D;Tacettin C;Weinstock M;Bisharat L;Morin A;Mahoney KM;Ebert B;Stone R;Kufe D;Freeman GJ;Rosenblatt J;Avigan D
我们已经开发了一种个性化的疫苗，其中患者来源的白血病细胞融合自体树突状细胞，引起针对共享抗原和新抗原的多克隆T细胞应答。我们假设树突状细胞/急性髓性白血病融合疫苗将通过扩增肿瘤抗原特异性淋巴细胞来证明与检查点阻断的协同作用，这将为检查点阻断介导的激活提供关键底物。使用免疫活性小鼠白血病模型，我们检查了疫苗接种联合检查点阻断在白血病植入、疾病负荷、存活和肿瘤特异性免疫诱导方面的免疫应答和治疗效果。仅接受检查点阻断治疗的小鼠白血病进展迅速，生存期仅适度延长。树突状细胞/急性髓性白血病融合疫苗接种导致肿瘤特异性淋巴细胞的扩增和动物亚组的疾病根除，而疫苗接种和检查点阻断的组合在所有治疗的动物中诱导了完全保护性的肿瘤特异性免疫应答。接种疫苗后，检查点阻断导致调节记忆和效应T细胞活化和增殖的基因上调。长期存活者表现出T细胞克隆多样性增加，并对随后的肿瘤攻击有抵抗力。树突状细胞/急性髓性白血病融合疫苗和检查点阻断治疗的组合提供了独特的协同作用，诱导白血病特异性免疫的持久激活，保护免受致命肿瘤攻击和肿瘤反应性克隆的选择性扩增。
We have developed a personalized vaccine in which patientderived leukemia cells are fused to autologous dendritic cells, evoking a polyclonal T-cell response against shared antigens and neoantigens. We postulated that the dendritic cell/acute myeloid leukemia fusion vaccine would demonstrate synergy with checkpoint blockade by expanding tumor antigen-specific lymphocytes that would provide a critical substrate for checkpoint blockade-mediated activation. Using an immunocompetent murine leukemia model, we examined the immunological response to and therapeutic efficacy of vaccination in conjunction with checkpoint blockade with respect to leukemia engraftment, disease burden, survival and the induction of tumor-specific immunity. Mice treated with checkpoint blockade alone had rapid progression of leukemia and only a modest extension of survival. Vaccination with dendritic cell/acute myeloid leukemia fusions resulted in the expansion of tumor-specific lymphocytes and disease eradication in a subset of animals, while the combination of vaccination and checkpoint blockade induced a fully protective tumor-specific immune response in all treated animals. Vaccination followed by checkpoint blockade resulted in upregulation of genes regulating activation and proliferation in memory and effector T cells. Long-term survivors exhibited increased T-cell clonal diversity and were resistant to subsequent tumor challenge. The combination of dendritic cell/acute myeloid leukemia fusion vaccine and checkpoint blockade treatment offers unique synergy, inducing durable activation of leukemia-specific immunity, protection from lethal tumor challenge and the selective expansion of tumor-reactive clones.