Tumor-promoting versus tumor-antagonizing roles of γδ T cells in cancer immunotherapy: results from a prospective phase I/II trial.
Emerging evidence suggests that nitrogen-containing bisphosphonates have direct and indirect anticancer effects including immunomodulatory effects. Using in vivo targeting of bisphosphonate-reactive γδ 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-γ production) and expansion of γδ 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.
Medizinische Klinik und Poliklinik II & Comprehensive Cancer Center Mainfranken, Zentrum für Innere Medizin (A3-1.919), Oberdürrbacher Str. 6, D-97080 Würzburg, Germany. kunzmann_v@medizin.uni-wuerzburg.de
Volker
V
Kunzmann
Manfred
M
Smetak
Brigitte
B
Kimmel
Karin
K
Weigang-Koehler
Mariele
M
Goebeler
Josef
J
Birkmann
Jürgen
J
Becker
Ingo G H
IG
Schmidt-Wolf
Hermann
H
Einsele
Martin
M
Wilhelm
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000276:immunology; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004164:Diphosphonates / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000276:immunology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000187:drug effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D000077211:Zoledronic Acid
D016207:Cytokines; D004164:Diphosphonates; D007093:Imidazoles; D007376:Interleukin-2; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000077211:Zoledronic Acid