抗PD-1治疗延长了包括非小细胞肺癌(NSCLC)在内的转移性肿瘤的持续反应时间以及延长了总生存期。然而，在临床试验中，患者对PD-1的响应率低至20%，约50%的患者不能从抗PD-1治疗中获益。于是科学家猜想存在抗肿瘤免疫亚组可能是患者对抗PD-1免疫治疗效果不同的原因。那些有抗肿瘤活性的患者，本研究中的效应T细胞，具有抗肿瘤活性，在淋巴结中阻止肿瘤的生长，这些T细胞仅属于能够下调CD62L(CD62Llow)的T细胞。对于很多没有特效肿瘤抗原或者肽的情况下，T细胞表面的CD62L分子可以最为鉴定肿瘤特异性免疫细胞的替代标志物。相关研究结果发表在6月2-6日在美国芝加哥举行的第53届美国临床肿瘤学会年会(ASCO)上。

        本研究共纳入50例NSCLC打算接受PD-1抗体纳武单抗(nivolumab)治疗的患者，对其外周血单核细胞进行分析。患者接受 2周/次的3 mg/kg nivolumab治疗 。用实体瘤疗效评价标准(RECIST)1.1版对患者每8周治疗的响应进行评估。

        试验结果发现，达到部分缓解(PR)或者稳定疾病(SD)的NSCLC患者其外周血单核细胞CD62Llow CD4+ T细胞比疾病进展(PD)的患者显著增多 (P = 4.1x10-7) 。

        CD62Llow能提供92.9%的灵敏度以及96.7%的特异性。此外，与PR患者相比，SD患者具有显著的(p = 0.0067)调节性T细胞亚群，可以基于此对PR及SD患者进行预测。

        研究结论认为，抗PD-1治疗引起了PR, SD和PD患者CD4 + T的细胞的变化。

        接下来正在着手CD62Llow CD4+ T的特性包括mRNA微阵列，检查点分子和趋化因子受体等的研究。

        摘要原文：

        摘要编号：#11525

        CD4+ T cells in PBMC to predict the outcome of anti-PD-1 therapy.

        Author(s): Hiroshi Kagamu, Ou Yamaguchi, Ayako Shiono, Atsuto Mouri, Sachiko Miyauchi, Harue Utsugi, Fuyumi Nishihara, Takahiro Uchida, Yoshitake Murayama, Kunihiko Kobayashi; Niigata University, Niigata, Japan; Division of Respiratory Medicine, Saitama Medical University International Medical Center, Hidaka, Japan

        Abstract Disclosures

        Abstract:

        Background: Antibody blockade of programmed death 1 (PD-1), has led to durable responses and significant prolongation of overall survival in metastatic cancers including non-small cell lung cancer (NSCLC). However, in clinical trials, response rates were as low as 20 %, and approximately 50 % of the patients did not achieve benefits to prolong progression free survival. These results bring us a hypothesis that there are subgroups with distinct pre-existing anti-tumor immunity resulting in different responses to anti-PD-1 therapy. We reported that effector T cells, which are capable of mediating antitumor reactivity, are primed in LNs draining growing tumors and that these T cells exclusively belong to the T cells that down-regulated CD62L (CD62Llow) subpopulation. In the absence of purified tumor antigenic proteins or peptides on many tumors, the expression of the homing molecule CD62L on T cells may serve as a surrogate marker for identifying tumor-specific immune cells. Methods: We analyzed the peripheral blood mononuclear cells (PBMC) of 50 consecutive NSCLC patients who were planned to be treated with anti-PD-1 Ab, Nivolumab after obtaining written informed consent. The patients received Nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks. Tumor response was assessed with the use of the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, at week 8 and every 8 weeks thereafter. Results: The NSCLC patients who achieved partial response (PR) or stable disease (SD) had significantly (p = 4.1x10-7) more CD62Llow CD4+ T cells in PBMC than progressive disease (PD) patients. The percentages of CD62Llow in CD4+ T cells provided sensitivity 92.9 %, and specificity 96.7 % to predict the patients who had PD. Moreover, SD patients had significantly (p = 0.0067) less regulatory T cell subpopulation than PR patients, thus, it was possible to predict PR from SD. Conclusions: These results show that the major differences in pre-existing immunity among PR, SD, and PD patients to anti-PD-1 Ab existed in CD4+ T cell balance between primed effector and regulatory T cells. Further characterization of CD62Llow CD4+ T cells including mRNA microarray, checkpoint molecules, and chemokine receptors is going on.