Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1
Persistent mutant oncogene specific T cells in two patients benefitting from anti-PD-1
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DOI：
10.1186/s40425-018-0492-x
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发表时间：
2019-02-11
影响因子：
10.9
通讯作者：
Housseau, Franck
中科院分区：
文献类型：
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作者：
Smith, Kellie N.;Llosa, Nicolas J.;Housseau, Franck
背景目前有几种预测性生物标志物已被批准或正在研究用于选择检查点封锁的患者。肿瘤 PD-L1 表达用于对非小细胞肺 (NSCLC) 患者进行分层，肿瘤突变负荷 (TMB) 也正在探索中，并取得了有希望的结果，并且错配修复缺陷被批准用于肿瘤部位不可知的疾病。虽然具有高 PD-L1 表达、高 TMB 或错配修复缺陷的肿瘤对检查点阻断反应良好，但具有较低 PD-L1 表达、较低突变负担或错配修复能力的肿瘤的反应频率要低得多。 病例介绍我们研究了两名对检查点阻断单药治疗出现意外反应的患者：一名 PD-L1 阴性和低突变负荷 NSCLC 患者，以及一名错配修复熟练的结直肠癌 (CRC) 患者，两人都缺乏与反应相关的生物标志物检查点封锁，但取得了持久的临床益处。治疗开始数年后，两者均维持外周血中 T 细胞对致癌驱动突变（NSCLC 中的 BRAF-N581I 和 CRC 中的 AKT1-E17K）的反应。在原发性肿瘤中也发现了突变特异性 T 细胞，并在治疗后在外周经历了动态扰动。结论这些发现表明，T 细胞对致癌驱动突变的反应可能比以前认为的更普遍，并且可以在免疫治疗中利用，特别是对于缺乏与反应相关的传统生物标志物的患者。有必要进行全面研究，以进一步确定其他预测生物标志物和可能受益于检查点封锁的患者群体。
BackgroundSeveral predictive biomarkers are currently approved or are under investigation for the selection of patients for checkpoint blockade. Tumor PD-L1 expression is used for stratification of non-small cell lung (NSCLC) patients, with tumor mutational burden (TMB) also being explored with promising results, and mismatch-repair deficiency is approved for tumor site-agnostic disease. While tumors with high PD-L1 expression, high TMB, or mismatch repair deficiency respond well to checkpoint blockade, tumors with lower PD-L1 expression, lower mutational burdens, or mismatch repair proficiency respond much less frequently.Case presentationWe studied two patients with unexpected responses to checkpoint blockade monotherapy: a patient with PD-L1-negative and low mutational burden NSCLC and one with mismatch repair proficient colorectal cancer (CRC), both of whom lack the biomarkers associated with response to checkpoint blockade, yet achieved durable clinical benefit. Both maintained T-cell responses in peripheral blood to oncogenic driver mutations - BRAF-N581I in the NSCLC and AKT1-E17K in the CRC - years after treatment initiation. Mutation-specific T cells were also found in the primary tumor and underwent dynamic perturbations in the periphery upon treatment.ConclusionsThese findings suggest that T cell responses to oncogenic driver mutations may be more prevalent than previously appreciated and could be harnessed in immunotherapeutic treatment, particularly for patients who lack the traditional biomarkers associated with response. Comprehensive studies are warranted to further delineate additional predictive biomarkers and populations of patients who may benefit from checkpoint blockade.