Trial Information

Phase I Trial of Intratumoral Injection of an Adenovirus Encoding Human Endostatin for Advanced Solid Tumors

It is widely recognized that angiogenesis not only is important in physiological processes
such as embryonic development, wound healing, and organ and tissue regeneration, but also
play a pivotal role in tumor growth, tissue invasion, and metastasis.1 This complex,
multistep process of angiogenesis involves interactions between tumor cells and endothelial
cells (ECs), growth factors, and extracellular matrix components. Tumors that are unable to
elicit angiogenesis exist in a dormant state, and are unable to grow beyond the size of 1-2
mm. Angiogenesis is regulated by a variety of pro-angiogenesis and anti-angiogenesis factors
and their imbalance can lead to disease. The abnormal features of the tumor vasculature
perhaps represent an imbalanced expression of proangiogenic factors and antiangiogenic
factors.1 Antiangiogenic therapies inhibit the growth of genetically stable endothelial
cells, and most tumors should starve to death with little acquired resistance.
Antiangiogenesis agents such as Avastin for the treatment of cancer have now been approved
by the FDA in the US and in other countries.2 Endostatin, a 20 kDa C-terminal fragment of
the carboxyterminus of collagen XVIII, has been shown to block endothelial cell
proliferation, survival, and migration, in part through downregulating proangiogenic factor
(such as Ids, HIF-1a, VEGF-A, bFGF) and upregulating antiangiogenic factors (such as
Thrombospondin-1,2, vasostatin, kininogen).4,5,6 Of the endogenous antiangiogenic factors in
the body, endostatin has broadest anti-cancer spectrum and the least toxic and no resistance
anti-cancer drug in mice and human. Endostatin is the first endogenous angiogenesis
inhibitor to introduce into human clinical trials.

However, therapy with recombinant endostatin protein is hampered by their shot half-life,
difficulties in protein production and long-term storage of bioactive protein. Furthermore,
the inhibition of tumor angiogenesis is a long-term and chronic process of treatment. Gene
therapy may be overcome these difficulties by introducing human endostatin cDNA into the
host and using the body as an endogenous factory to generate highly bioactive gene product.
Expression of endostatin by adenoviral gene transfer (Ad-rhEndo, E10A) generates a strong
systemic therapeutic effect in several models of solid tumors in mice.7,8,9,10 Intratumoral
injections of E10A into subcutaneous xenografts of hepatocellular carcinoma BEL-7402,
nasopharyngeal carcinoma CNE-2, Tongue cancer Tca8113 in nude mice demonstrated significant
tumor growth inhibition and reduce angiogenesis in tumors. No toxic effects of E10A
administration in these pharmacology studies were identified. On the base of promising
preclinical results in solid tumors, we undertook a dose-escalation phase I trial of E10A in
the treatment of patients with advanced solid tumors.