Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Lancet Oncol. 2014 Jan;15(1):69-77. doi: 10.1016/S1470-2045(13)70551-5. Epub 2013 Dec 11.
BACKGROUND: Endogenous or iatrogenic antitumour immune responses can improve the course of follicular lymphoma, but might be diminished by immune checkpoints in the tumour microenvironment. These checkpoints might include effects of programmed cell death 1 (PD1), a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. We did this phase 2 trial to investigate the activity of pidilizumab, a humanised anti-PD1 monoclonal antibody, with rituximab in patients with relapsed follicular lymphoma. METHODS: We did this open-label, non-randomised trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Adult (≥18 years) patients with rituximab-sensitive follicular lymphoma relapsing after one to four previous therapies were eligible. Pidilizumab was administered at 3 mg/kg intravenously every 4 weeks for four infusions, plus eight optional infusions every 4 weeks for patients with stable disease or better. Starting 17 days after the first infusion of pidilizumab, rituximab was given at 375 mg/m(2) intravenously weekly for 4 weeks. The primary endpoint was the proportion of patients who achieved an objective response (complete response plus partial response according to Revised Response Criteria for Malignant Lymphoma). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00904722. FINDINGS: We enrolled 32 patients between Jan 13, 2010, and Jan 20, 2012. Median follow-up was 15.4 months (IQR 10.1-21.0). The combination of pidilizumab and rituximab was well tolerated, with no autoimmune or treatment-related adverse events of grade 3 or 4. The most common adverse events of grade 1 were anaemia (14 patients) and fatigue (13 patients), and the most common adverse event of grade 2 was respiratory infection (five patients). Of the 29 patients evaluable for activity, 19 (66%) achieved an objective response: complete responses were noted in 15 (52%) patients and partial responses in four (14%). INTERPRETATION: The combination of pidilizumab plus rituximab is well tolerated and active in patients with relapsed follicular lymphoma. Our results suggest that immune checkpoint blockade is worthy of further study in follicular lymphoma. FUNDING: National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech, and University of Texas MD Anderson Cancer Center.
背景：内源性或医源性抗肿瘤免疫反应可以改善滤泡性淋巴瘤的病程，但肿瘤微环境中的免疫检查点可能会减弱这种反应。这些检查点可能包括程序性细胞死亡蛋白 1（PD1）的作用，PD1 是一种共抑制受体，它会损害 T 细胞的功能，并且在肿瘤内 T 细胞上高度表达。我们进行了这项 2 期临床试验，以研究 pidilizumab（一种人源化抗 PD1 单克隆抗体）联合利妥昔单抗治疗复发性滤泡性淋巴瘤患者的疗效。
方法：我们在德克萨斯大学 MD 安德森癌症中心（美国休斯顿）进行了这项开放标签、非随机试验。符合条件的患者为接受过一次至四次先前治疗后复发的利妥昔单抗敏感滤泡性淋巴瘤的成年（≥18 岁）患者。pidilizumab 以 3mg/kg 静脉输注，每 4 周一次，共输注 4 次，对于病情稳定或改善的患者，还可选择再输注 8 次，每 4 周一次。在首次 pidilizumab 输注后 17 天开始，每周静脉输注利妥昔单抗 375mg/m2，连续输注 4 周。主要终点是达到客观缓解的患者比例（根据恶性淋巴瘤修订反应标准，完全缓解加部分缓解）。分析采用意向治疗。这项试验在 ClinicalTrials.gov 注册，编号为 NCT00904722。
结果：我们于 2010 年 1 月 13 日至 2012 年 1 月 20 日期间入组了 32 名患者。中位随访时间为 15.4 个月（IQR：10.1-21.0）。pidilizumab 联合利妥昔单抗的耐受性良好，无自身免疫或治疗相关的 3 级或 4 级不良事件。最常见的 1 级不良事件是贫血（14 例）和疲劳（13 例），最常见的 2 级不良事件是呼吸道感染（5 例）。在 29 名可评估疗效的患者中，19 名（66%）达到了客观缓解：完全缓解 15 例（52%），部分缓解 4 例（14%）。
结论：pidilizumab 联合利妥昔单抗在复发性滤泡性淋巴瘤患者中耐受性良好且疗效显著。我们的结果表明，免疫检查点阻断值得进一步研究滤泡性淋巴瘤。
资助：美国国立卫生研究院、白血病和淋巴瘤协会、CureTech 公司和德克萨斯大学 MD 安德森癌症中心。
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