G17DT: an antigastrin immunogen for the treatment of gastrointestinal malignancy

Abstract

G17DT (Gastrimmune) is an antigastrin-17 immunogen, raising antibodies that blockade gastrin-stimulated tumor growth. It has completed Phase III trials in patients with pancreatic cancer, and Phase III trials in gastric cancer are planned. Preclinical studies have confirmed that the G17DT-induced antibodies both reduce gastrin-17-stimulated gastric acid secretion and inhibit gastrin from interacting with the cholecystokinin-2 receptor. The efficacy of both passive and active immunization with G17DT has been established in a number of tumor systems, with additive effects demonstrated in combination chemotherapy in pancreatic, colon and gastric tumor models. Phase I/II studies in advanced gastrointestinal malignancies have shown no systemic or autoimmune reactions to active immunization with G17DT. The use of an optimized dose and dosing schedule has yielded a high proportion of antibody responders (70%), with minimal side effects and antibody titers measurable within 2 – 4 weeks. Phase II trials of G17DT in combination with chemotherapy have also been conducted in gastric and colorectal cancer. A Phase III, multicenter, double-blind, randomized, controlled trial of G17DT versus placebo in patients with advanced pancreatic cancer confirmed improved survival of patients in the G17DT group through an intention-to-treat analysis. The results of a randomized, double-blind, multinational, multicenter study of G17DT in combination with gemcitabine versus placebo and gemcitabine in patients with advanced pancreatic cancer failed to show improved overall survival except on subset analysis of patients with high antibody titers. Therefore, G17DT represents an emerging new modality for gastrointestinal malignancy.

Keywords::

• angiogenesis
• apoptosis
• colorectal cancer
• G17DT
• gastric cancer
• gastrin
• pancreatic cancer

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