Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
Cancer Sci. 2020 Aug;111(8):2736-2746. doi: 10.1111/cas.14451. Epub 2020 Jun 18.
Lung cancer is the leading cause of cancer-related deaths worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) often have good clinical activity against non-small cell lung cancer (NSCLC) with activating EGFR mutations. Osimertinib, which is a third-generation EGFR-TKI, has a clinical effect even on NSCLC harboring the threonine to methionine change at codon 790 of EGFR (EGFR T790M) mutation that causes TKI resistance. However, most NSCLC patients develop acquired resistance to osimertinib within approximately 1 year, and 40% of these patients have the EGFR T790M and cysteine to serine change at codon 797 (C797S) mutations. Therefore, there is an urgent need for the development of novel treatment strategies for NSCLC patients with the EGFR T790M/C797S mutation. In this study, we identified the EGFR T790M/C797S mutation-derived peptide (790-799) (MQLMPFGSLL) that binds the human leukocyte antigen (HLA)-A*02:01, and successfully established EGFR T790M/C797S-peptide-specific CTL clones from human PBMC of HLA-A2 healthy donors. One established CTL clone demonstrated adequate cytotoxicity against T2 cells pulsed with the EGFR T790M/C797S peptide. This CTL clone also had high reactivity against cancer cells that expressed an endogenous EGFR T790M/C797S peptide using an interferon-γ (IFN-γ) enzyme-linked immunospot (ELISPOT) assay. In addition, we demonstrated using a mouse model that EGFR T790M/C797S peptide-specific CTL were induced by EGFR T790M/C797S peptide vaccine in vivo. These findings suggest that an immunotherapy targeting a neoantigen derived from EGFR T790M/C797S mutation could be a useful novel therapeutic strategy for NSCLC patients with EGFR-TKI resistance, especially those resistant to osimertinib.
肺癌是全球癌症相关死亡的主要原因。表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）对具有激活 EGFR 突变的非小细胞肺癌（NSCLC）通常具有良好的临床活性。奥希替尼是一种第三代 EGFR-TKI，即使在 NSCLC 中也具有临床疗效，其中 EGFR 密码子 790 处的苏氨酸到蛋氨酸改变（EGFR T790M）突变导致 TKI 耐药。然而，大多数 NSCLC 患者在大约 1 年内对奥希替尼产生获得性耐药，其中 40%的患者具有 EGFR T790M 和半胱氨酸到丝氨酸改变（C797S）突变。因此，迫切需要为具有 EGFR T790M/C797S 突变的 NSCLC 患者开发新的治疗策略。在这项研究中，我们鉴定了与人类白细胞抗原（HLA）-A*02:01 结合的 EGFR T790M/C797S 突变衍生肽（790-799）（MQLMPFGSLL），并从 HLA-A2 健康供者的人 PBMC 中成功建立了 EGFR T790M/C797S-肽特异性 CTL 克隆。一个建立的 CTL 克隆对用 EGFR T790M/C797S 肽脉冲的 T2 细胞显示出足够的细胞毒性。该 CTL 克隆还对表达内源性 EGFR T790M/C797S 肽的癌细胞具有高反应性，使用干扰素-γ（IFN-γ）酶联免疫斑点（ELISPOT）测定法。此外，我们使用小鼠模型证明，EGFR T790M/C797S 肽疫苗在体内诱导 EGFR T790M/C797S 肽特异性 CTL。这些发现表明，针对源自 EGFR T790M/C797S 突变的新抗原的免疫疗法可能是 EGFR-TKI 耐药的 NSCLC 患者的一种有用的新型治疗策略，特别是对奥希替尼耐药的患者。
