Combination of temozolomide with immunocytokine F16-IL2 for the treatment of glioblastoma.
BACKGROUND
Glioblastoma patients are still not cured by the treatments available at the moment. We investigated the therapeutic properties of temozolomide in combination with F16-IL2, a clinical-stage immunocytokine consisting of human interleukin (IL)-2 fused to the human antibody F16, specific to the A1 domain of tenascin-C.


METHODS
We conducted three preclinical therapy studies, using subcutaneous and intracranial U87MG glioblastoma tumours xenografted in BALB/c nude mice. The same therapeutic schedule was used, consisting of five total administrations every third day, of 0.525 mg temozolomide, 20 microg F16-IL2, the combination, or the control solution.


RESULTS
Immunohistochemical analysis of U87MG xenografts and of human glioblastoma specimens showed selective tumour staining of F16. A quantitative biodistribution confirmed the preferential tumour accumulation of radiolabelled F16-IL2. In the study with subcutaneous xenografts, the combination of F16-IL2 with temozolomide induced complete remission of the animals, which remained tumour free for over 160 days. The same treatment led to a consistent size reduction of intracranial xenografts and to a longer survival of animals. The immunocytokine promoted the recruitment of leukocytes into tumours of both models.


CONCLUSIONS
The combined use of temozolomide with F16-IL2 deserves clinical investigations, which will be facilitated by the excellent safety profile in cynomolgus monkeys, and by the fact that F16-IL2 is in clinical trials in patients with cancer.
Pedretti
M
M
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH-Swiss Federal Institute of Technology Zurich, Wolfgang-Pauli-Strasse 10, 8093 Zurich, Switzerland.
Verpelli
C
C
Mårlind
J
J
Bertani
G
G
Sala
C
C
Neri
D
D
Bello
L
L
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D000077204:Temozolomide; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D007376:Interleukin-2; D003606:Dacarbazine; D000077204:Temozolomide