Pankreaskarzinom

[Berte]

Sehr geehrter Prof. Dr. Wust,

der letzte Beitrag bzgl. des Präparates "ONYX-015" datiert aus dem Jahre 2002 (Januar). Ist Ihnen bekannt, ob es zwischenzeitlich zur klinischen Anwendung kam? Wenn ja - an wen kann man sich wenden?

Vielen Dank bereits an dieser Stelle!

Mit freundlichen Grüßen

Birgit

[Prof. Wust]

RE: Pankreaskarzinom


Klinische Arbeiten zu diesem Vektor sind nicht auffindbar. Sicher werden solche Studien noch längere Zeit in Anspruch nehmen. Derzeit wird noch die Feasibility geprüft. Die Gentherapie ist ja etwas zurückgeworfen worden aufgrund von unerwarteten Nebenwirkungen in der jüngeren Vergangenheit. In dem 2. Beitrag sehen Sie, wie basal zur Zeit noch die klinischen Fragestellungen sind (man freut sich, wenn die Patienten die Therapie einigermaßen vertragen). Zur Zeit würde ich nicht an einen Einsatz in der Tumortherapie denken.

1. Evidence that replication of the antitumor adenovirus ONYX-015 is not controlled by the p53 and p14(ARF) tumor suppressor genes.
AU: Edwards,-S-J; Dix,-B-R; Myers,-C-J; Dobson-Le,-D; Huschtscha,-L; Hibma,-M; Royds,-J; Braithwaite,-A-W
AD: Departments of Pathology, University of Otago, Dunedin, New Zealand.
SO: J-Virol. 2002 Dec; 76(24): 12483-90
AB: The adenovirus mutant ONYX-015 is in phase III clinical trials as a novel antitumor therapy. Its apparent efficacy is thought to be due to its ability to replicate selectively in tumor cells defective in the signaling pathway for p53. Recent data have shown that p14(ARF), a positive regulator of p53, inhibits ONYX-015 replication in cells with a wild-type p53, a phenotype that characterizes normal cells. We, however, found that ONYX-015 activates p53 in tumor cells and in normal cells and that this can occur without p14(ARF) induction. We also show that ONYX-015 is not attenuated in cells with functional p53, whether or not p14(ARF) is expressed, and that where attenuation does occur, it is cell type specific.


2. Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints.
AU: Reid,-T; Galanis,-E; Abbruzzese,-J; Sze,-D; Wein,-L-M; Andrews,-J; Randlev,-B; Heise,-C; Uprichard,-M; Hatfield,-M; Rome,-L; Rubin,-J; Kirn,-D
AD: Palo Alto Veterans Administration Hospital and Stanford University Medical Center, California 94305, USA.
SO: Cancer-Res. 2002 Nov 1; 62(21): 6070-9
AB: Replication-selective oncolytic adenoviruses are being developed for the treatment of cancer, but the safety and feasibility of repeated adenovirus delivery to tumors via the bloodstream was unknown, particularly in light of a patient death after hepatic artery infusion of a replication-defective adenovirus vector. We performed a Phase II trial of an oncolytic replication-selective adenovirus (dl1520, also known as Onyx-015) administered by hepatic artery infusion in patients with gastrointestinal carcinoma metastatic to the liver (n = 27). dl1520 was infused into the hepatic artery (2 x 10(12) particles) on days 1 and 8 as a single agent, and thereafter starting on day 22 in combination with i.v. 5-fluorouracil and leucovorin every 28 days. Repeated viral infusions were feasible, and no deaths occurred on study; reversible grade 3/4 hyperbilirubinemia occurred in 2 patients. Systemic inflammatory cytokine responses varied greatly between patients and even between cycles within a given patient. Proinflammatory cytokines [e.g., tumor necrosis factor, IFN-gamma, and interleukin (IL) 6] typically rose within 3 h and were followed at 18 h by a rise in IL-10. However, in the single patient who suffered a severe but reversible systemic inflammatory response, a unique cytokine profile was detected: marked acute increases of IL-6 (20-fold higher than average for all of the patients) and inhibition of IL-10 production. Delayed secondary peaks of viremia were reproducibly detected 3-6 days after treatment, even in the presence of high level neutralizing antibody titers and antiviral cytokines. Mathematical modeling was used to calculate the number of virus particles produced and shed into the blood with each replication cycle. The combination of virotherapy and chemotherapy had antitumoral activity in some chemotherapy-resistant colorectal tumors. The intra-arterial infusion of oncolytic adenoviruses warrants additional study.