Merlino Dante J, Johnson Jennifer M, Tuluc Madalina, Gargano Stacey, Stapp Robert, Harshyne Larry, Leiby Benjamin E, Flanders Adam, Zinner Ralph, Axelrod Rita, Curry Joseph, Cognetti David M, Mannion Kyle, Kim Young J, Rodeck Ulrich, Argiris Athanassios, Luginbuhl Adam J
Department of Otolaryngology - Head and Neck Surgery, Thomas Jefferson University, Philadelphia, PA, United States.
Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA, United States.
Front Oncol. 2020 Dec 2;10:566315. doi: 10.3389/fonc.2020.566315. eCollection 2020.
PD-1 blockade represents a promising treatment in patients with head and neck squamous cell carcinoma (HNSCC). We analyzed results of a neoadjuvant randomized window-of-opportunity trial of nivolumab plus/minus tadalafil to investigate whether immunotherapy-mediated treatment effects vary by site of involvement (primary tumor, lymph nodes) and determine how radiographic tumor shrinkage correlates with pathologic treatment effect.
Forty-four patients enrolled in trial NCT03238365 were treated with nivolumab 240 mg intravenously on days 1 and 15 with or without oral tadalafil, as determined by random assignment, followed by surgery on day 31. Radiographic volumetric response (RVR) was defined as percent change in tumor volume from pretreatment to posttreatment CT scan. Responders were defined as those with a 10% reduction in the volume of the primary tumor or lymph nodes (LN). Pathologic treatment effect (PTE) was defined as the area showing fibrosis or lymphohistiocytic inflammation divided by total tumor area.
Sixteen of 32 patients (50%) with pathologic evidence of LN involvement exhibited discordant PTE between primary sites and LN. In four patients with widely discordant adjacent LN, increased PTE was associated with increased infiltration of tumor CD8 T cells and CD163 macrophages, whereas stromal regulatory T cells were associated with low nodal PTE. RVR correlated with PTE at both primary tumor (slope = 0.55, < 0.001) and in LN (slope = 0.62, < 0.05). 89% (16/18) of radiographic non-responders with T1-T3 primary sites had no (n = 7) or minimal PTE (n = 9), whereas 15/17 (88%) of radiographic responders had moderate (n = 12) or complete (n = 3) PTE.
Nivolumab often induces discordant treatment effects between primary tumor sites and metastatic lymph nodes within subjects. This treatment discordance was also demonstrated in adjacent lymph nodes, which may correlate with local immune cell makeup. Finally, although these data were generated by a relatively small population size, our data support the use of early radiographic response to assess immunotherapy treatment effect in HNSCC.
程序性死亡受体1（PD-1）阻断疗法对头颈部鳞状细胞癌（HNSCC）患者而言是一种很有前景的治疗方法。我们分析了一项纳武单抗加/减他达拉非的新辅助随机机会窗试验的结果，以研究免疫疗法介导的治疗效果是否因受累部位（原发肿瘤、淋巴结）而异，并确定影像学肿瘤缩小与病理治疗效果之间的相关性。
参与试验NCT03238365的44例患者，根据随机分配情况，于第1天和第15天静脉注射240mg纳武单抗，同时口服或不口服他达拉非，然后于第31天进行手术。影像学体积反应（RVR）定义为从治疗前到治疗后CT扫描肿瘤体积的变化百分比。反应者定义为原发肿瘤或淋巴结（LN）体积减少10%的患者。病理治疗效果（PTE）定义为显示纤维化或淋巴细胞组织细胞炎症的面积除以肿瘤总面积。
32例有LN受累病理证据的患者中，16例（50%）原发部位和LN之间的PTE不一致。在4例相邻LN差异很大的患者中，PTE增加与肿瘤CD8 T细胞和CD163巨噬细胞浸润增加相关，而基质调节性T细胞与低淋巴结PTE相关。RVR在原发肿瘤（斜率=0.55，P<0.001）和LN（斜率=0.62，P<0.05）中均与PTE相关。89%（16/18）T1-T3原发部位的影像学无反应者无（n=7）或仅有最小PTE（n=9），而15/17（88%）的影像学反应者有中度（n=12）或完全（n=3）PTE。
纳武单抗常导致受试者原发肿瘤部位和转移性淋巴结之间的治疗效果不一致。这种治疗差异在相邻淋巴结中也得到证实，这可能与局部免疫细胞组成有关。最后，尽管这些数据来自相对较小的样本量，但我们的数据支持使用早期影像学反应来评估HNSCC的免疫治疗效果。
