期刊
JOURNAL OF IMMUNOTHERAPY
卷 35, 期 2, 页码 205-213出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CJI.0b013e318245bb1e
关键词
gamma delta T cells; zoledronic acid; IL-2; immunotherapy; VEGF
资金
- Interdisziplinaeres Zentrum fur Klinische Forschung Wuerzburg (IZKF) [01KS9603]
- Deutsche Forschungsgemeinschaft (DFG) [KFO 124/1-1 TP5]
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.
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