Efficacy of a replication-competent adenovirus (ONYX-015) following intratumoral injection: Intratumoral spread and distribution effects

Abstract

ONYX-015 is an E1B-deleted adenovirus that replicates in and causes lysis of p53-deficient cancer cells selectively. To study the efficiency of intratumoral (i.t.) spread by ONYX-015, we infected specific fractions of tumor cells (two p53-deficient tumor lines and one p53 functional line) in vitro before subcutaneous inoculation into nude mice. Infection of as few as 5% of p53 Ϫ tumor cells prevented tumor development in all cases; infection of 1% of p53 Ϫ tumor cells resulted in significant growth inhibition but did not prevent tumor formation. In contrast, infection with ONYX-015 had no significant effect on p53 ϩ tumor formation. These data suggested that replication-dependent tumor cell lysis and spread was occurring, but that tumor destruction might be improved by increasing i.t. virus distribution. Two treatment parameters were then varied to determine whether virus distribution, and consequently efficacy, could be improved. Divided i.t. injections of virus were more efficacious than a single injection of the same total dose. Likewise, increasing the volume of the viral suspension for i.t. injection allowed better distribution within the tumor mass and increased efficacy. These results have implications for the treatment of cancer patients with viral agents.

ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus

“…In addition, mixing experiments were performed in which only a fraction of subcutaneously injected cells has been pre-incubated with ONYX-015. As few as 5% of the injected cells needed to be infected to completely abolish tumour growth of cells with mutant p53, whereas no effect on tumour formation by cells with wild-type p53 cells was unchanged (Heise et al, 1999a). These data correlate well with in vitro studies and demonstrated significant therapeutic efficacy of ONYX-015 in vivo with evidence for p53-dependent virus replication.…”

“…Although these cells harbour wild-type p53, the pathway is partly inactivated because of a mutation of the p14ARF tumour suppressor gene. Different dosing schedules were tested and showed that virus application for five consecutive days was superior to a one-time application of the same total virus dose (Heise et al, 1999a). Furthermore, of particular importance for the subsequent clinical development of ONYX-015, it was noted that efficacy against this tumour was significantly enhanced when the virus was combined with the chemotherapeutic agents 5-FU or cisplatin (Heise et al, 1997).…”

Vascular endothelial growth factor promoter-based conditionally replicative adenoviruses for pan-carcinoma application

“…In this regard, a CRAd may achieve better intratumoral spread and penetration due to its replication ability. 32 For clinical application, prevention of hepatic toxicity is also an important consideration. Tumor cells infected with replication-competent Ad may release new viruses in vivo.…”

The oncolytic virotherapy treatment platform for cancer: Unique biological and biosafety points to consider

“…First, although viruses rapidly spread in cell culture monolayers, viral spread within a solid tumor mass can be limiting. 17,18 In fact, mathematical modeling of the ''race'' between viral oncolysis and spread versus tumor cell proliferation and outgrowth demonstrates that the infection of the tumor must be diffuse throughout the tumor in order to control it; injection of the tumor ''core'' or periphery only results in tumor ''escape''. 19 The relative inefficiency of viral spread may relate to their relatively large sizes (e.g., 90 nm for adenovirus ), dwarfing antitumoral chemicals, peptides, and even antibodies.…”