Arasanz Hugo, Zuazo Miren, Bocanegra Ana, Gato María, Martínez-Aguillo Maite, Morilla Idoia, Fernández Gonzalo, Hernández Berta, López Paúl, Alberdi Nerea, Hernández Carlos, Chocarro Luisa, Teijeira Lucía, Vera Ruth, Kochan Grazyna, Escors David
Oncoimmunology Group, Navarrabiomed, Instituto de Investigaciones Sanitarias de Navarra (IdISNA) UPNA, Irunlarrea st, 3, 31008 Pamplona, Spain.
Department of Medical Oncology, Complejo Hospitalario de Navarra, Instituto de Investigaciones Sanitarias de Navarra (IdISNA), Irunlarrea st, 3, 31008 Pamplona, Spain.
Cancers (Basel). 2020 Feb 4;12(2):344. doi: 10.3390/cancers12020344.
Hyperprogressive disease (HPD) is an adverse outcome of immunotherapy consisting of an acceleration of tumor growth associated with prompt clinical deterioration. The definitions based on radiological evaluation present important technical limitations. No biomarkers have been identified yet. In this study, 70 metastatic NSCLC patients treated with anti-PD-1/PD-L1 immunotherapy after progression to platinum-based therapy were prospectively studied. Samples from peripheral blood were obtained before the first (baseline) and second cycles of treatment. Peripheral blood mononuclear cells (PBMCs) were isolated and differentiation stages of CD4 lymphocytes quantified by flow cytometry and correlated with HPD as identified with radiological criteria. A strong expansion of highly differentiated CD28 CD4 T lymphocytes (CD4 THD) between the first and second cycle of therapy was observed in HPD patients. After normalizing, the proportion of posttreatment/pretreatment CD4 THD was significantly higher in HPD when compared with the rest of patients (median 1.525 vs. 0.990; = 0.0007), and also when stratifying by HPD, non-HPD progressors, and responders (1.525, 1.000 and 0.9700 respectively; = 0.0025). A cut-off value of 1.3 identified HPD with 82% specificity and 70% sensitivity. An increase of CD28 CD4 T lymphocytes ≥ 1.3 (CD4 THD burst) was significantly associated with HPD ( = 0.008). The tumor growth ratio (TGR) was significantly higher in patients with expansion of CD4 THD burst compared to the rest of patients (median 2.67 vs. 0.86, = 0.0049), and also when considering only progressors (median 2.67 vs. 1.03, = 0.0126). A strong expansion of CD28 CD4 lymphocytes in peripheral blood within the first cycle of therapy is an early differential feature of HPD in NSCLC treated with immune-checkpoint inhibitors. The monitoring of T cell dynamics allows the early detection of this adverse outcome in clinical practice and complements radiological evaluation.
超进展性疾病（HPD）是免疫治疗的一种不良后果，表现为肿瘤生长加速并伴有迅速的临床恶化。基于放射学评估的定义存在重要的技术局限性。目前尚未鉴定出生物标志物。在本研究中，对70例在铂类治疗进展后接受抗PD-1/PD-L1免疫治疗的转移性非小细胞肺癌（NSCLC）患者进行了前瞻性研究。在首次（基线）和第二个治疗周期前采集外周血样本。分离外周血单个核细胞（PBMC），通过流式细胞术对CD4淋巴细胞的分化阶段进行定量，并与根据放射学标准确定的HPD相关联。在HPD患者中观察到治疗的第一个周期和第二个周期之间高分化CD28-CD4 T淋巴细胞（CD4 THD）显著扩增。标准化后，与其他患者相比，HPD患者治疗后/治疗前CD4 THD的比例显著更高（中位数1.525对0.990；P = 0.0007），按HPD、非HPD进展者和缓解者分层时也是如此（分别为1.525、1.000和0.9700；P = 0.0025）。截断值为1.3时，鉴定HPD的特异性为82%，敏感性为70%。CD28-CD4 T淋巴细胞增加≥1.3（CD4 THD爆发）与HPD显著相关（P = 0.008）。与其他患者相比，CD4 THD爆发扩增的患者肿瘤生长率（TGR）显著更高（中位数2.67对0.86，P = 0.0049），仅考虑进展者时也是如此（中位数2.67对1.03，P = 0.0126）。免疫检查点抑制剂治疗的NSCLC患者中，治疗第一个周期外周血中CD28-CD4淋巴细胞的强烈扩增是HPD的早期鉴别特征。监测T细胞动态有助于在临床实践中早期发现这一不良后果，并补充放射学评估。
