ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents

Abstract

The 55-kilodalton (kDa) protein from the E1B-region of adenovirus binds to and inactivates the p53 gene, which is mutated in half of human cancers. We have previously shown that the replication and cytopathogenicity of an E1B, 55-kDa gene-attenuated adenovirus, ONYX-015, is blocked by functional p53 in RKO and U20S carcinoma lines. We now report that normal human cells were highly resistant to ONYX-015-mediated, replication-dependent cytolysis. In contrast, a wide range of human tumor cells, including numerous carcinoma lines with either mutant or normal p53 gene sequences (exons 5-9), were efficiently destroyed. Antitumoral efficacy was documented following intratumoral or intravenous administration of ONYX-015 to nude mouse-human tumor xenografts; efficacy with ONYX-015 plus chemotherapy (cisplatin, 5-fluorouracil) was significantly greater than with either agent alone.

Efficacy of a replication-selective adenovirus against ovarian carcinomatosis is dependent on tumor burden, viral replication and p53 status

“…First, significant efficacy was only seen in animals with low tumor burdens. The initial infection of tumor nodules following intraperitoneal administration was superficial compared with that seen in nude mouse-human tumor xenografts following intratumoral or intravenous administration; 15,16,26,27 other groups have shown similar superficial initial virus distribution with non-replicating adenoviruses. 28,29 This finding may at least partially explain the limited efficacy against bulky tumors.…”

“…adenoviruses over that seen with either chemotherapy or virus alone. 16,24 Based on these preclinical results, a phase I dose escalation trial of i.p. ONYX-015 is underway in patients with cisplatin-resistant, relapsed ovarian carcinoma.…”

“…14,15 Normal endothelial and epithelial cells are relatively resistant to ONYX-015-mediated effects. 16 Controversy has arisen, however, because the p53 gene sequence alone does not predict for the efficacy of ONYX-015. [17][18][19] This is not surprising given the complexities of the p53 response pathway(s).…”

“…Of note, ONYX-015 has shown activity against chemotherapy-resistant tumors in both preclinical and clinical studies. 16,22,24 Despite these findings, however, correlation of p53 function with efficacy has not been convincingly demonstrated in vivo to date. We therefore tested the sensitivity of tumor lines in vivo that were identical except for p53 status.…”

“…[14][15][16][22][23][24] However, this route of administration can be suboptimal for several reasons. First, the ability of the virus to spread within a dense solid tumor is limited by anatomical barriers such as the connective tissue and extracellular matrix that comprise the stromal tissue.…”