Tumor-promoting Versus Tumor-antagonizing Roles of γδ T Cells in Cancer Immunotherapy: Results From a Prospective Phase I/II Trial
Tumor-promoting Versus Tumor-antagonizing Roles of γδ T Cells in Cancer Immunotherapy: Results From a Prospective Phase I/II Trial
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DOI：
10.1097/cji.0b013e318245bb1e
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发表时间：
2012-02-01
影响因子：
3.9
通讯作者：
Wilhelm, Martin
中科院分区：
文献类型：
--
作者：
Kunzmann, Volker;Smetak, Manfred;Wilhelm, Martin
新出现的证据表明，含氮双膦酸盐具有直接和间接的抗癌作用，包括免疫调节作用。通过在唑来膦酸中加入低剂量白细胞介素-2，体内靶向双膦酸盐反应性γ δ T细胞，我们在21例晚期恶性肿瘤（肾细胞癌[RCC]、恶性黑色素瘤和急性髓性白血病）成人患者中评价了这种免疫治疗方法的安全性、药效学和抗肿瘤活性。共进行了58个治疗周期，中位治疗周期数为2.7（范围：1 - 6）。该方案耐受性良好，除发热外，无3至4级药物相关不良事件。在两个实体瘤队列（RCC和恶性黑色素瘤）中均未观察到客观缓解，而2例急性髓性白血病患者（25%）实现了客观肿瘤缓解（部分缓解）。药效学分析显示，在所有可评价的患者中，γ δ T细胞的体内活化（干扰素-γ产生）和扩增显著。高治疗前血清血管内皮生长因子（VEGF）水平和唑来膦酸加低剂量白细胞介素-2诱导的VEGF意外增加与缺乏临床反应相关。总之，这项研究表明，免疫治疗诱导的VEGF可以限制临床先天性肿瘤免疫反应，特别是对于血管生成依赖性实体瘤。我们的数据挑战了目前癌症治疗中的细胞免疫疗法范式。
Emerging evidence suggests that nitrogen-containing bisphosphonates have direct and indirect anticancer effects including immunomodulatory effects. Using in vivo targeting of bisphosphonate-reactive gamma delta T cells by adding low-dose interleukin-2 to zoledronic acid, we evaluated the safety, pharmacodynamics, and antitumor activity of this immunotherapy approach in 21 adults with advanced malignancies (renal cell carcinoma [RCC], malignant melanoma, and acute myeloid leukemia). A total of 58 treatment cycles were administered and the median number of treatment cycles was 2.7 (range, 1 to 6). The regimen was well tolerated, with no grade 3 to 4 drug-related adverse events, except for fever. No objective responses were observed in both cohorts of solid tumors (RCC and malignant melanoma), whereas 2 patients with acute myeloid leukemia (25%) achieved objective tumor responses (partial remission). Pharmacodynamic analyses showed significant in vivo activation (interferon-gamma production) and expansion of gamma delta T cells in all evaluable patients. High pretreatment serum vascular endothelial growth factor (VEGF) levels and an unexpected increase in VEGF induced by zoledronic acid plus low-dose interleukin-2 were correlated with the lack of a clinical response. In conclusion, this study indicates that immunotherapy-induced VEGF can limit clinical innate tumor immune responses, especially for angiogenesis-dependent solid tumors. Our data challenge the current cellular immunotherapy paradigms in the treatment of cancer.