“Infectious” Optimism for Treatment of Hepatocellular Carcinoma

Many viruses are known to destroy cells as a byproduct of viral replication, and those that preferentially target cancer cells (either naturally or through engineering) are termed oncolytic viruses. In a recent article in Nature Medicine, Heo and colleagues present results of a 30-patient prospective and randomized clinical trial of a vaccinia virus JX-594—which is oncolytic and simultaneously expresses granulocyte–macrophage colony-stimulating factor—in subjects suffering from hepatocellular carcinoma (HCC).1 The primary and most exciting finding is that the median survival of patients accrued to a high-dose cohort was significantly longer than that of patients accrued to a low-dose cohort. To the degree that the low-dose cohort serves as a “control” group, this finding suggests significant anticancer activity of JX-594 against HCC. JX-594 therefore has the potential to be, if not the first, one of the first oncolytic viruses shown to be beneficial in patients, pending the outcome of another phase III trial of a different oncolytic virus.2,3 The population targeted in this clinical trial is in dire need of therapeutic options. HCC is the sixth most common cancer worldwide and, owing to its poor prognosis, is the third leading cause of cancer-related death.4 In the United States, the incidence of HCC has tripled during the past two decades while the five-year survival rate has remained below 12%, making HCC the most rapidly increasing cause of cancer-related mortality.5 Breakthrough discoveries in molecular target identification and effective therapies are urgently needed to improve outcomes. The article by Heo and colleagues suggests that JX-594 may be up to the challenge. Descriptions of viral cancer therapy early in the last century centered on observations of occasional tumor regressions in cancer patients suffering from virus infections or in those receiving vaccinations. In 1950, Pack described the use of an attenuated rabies virus specifically to treat melanoma and partial remission was observed.6 Vaccinia virus is well known to both the scientific community and the public for its successes as a vaccine to eradicate smallpox. More recent studies have focused on the concept of destruction of cancer cells via lytic replication, a type of life cycle characteristic of many viruses, including herpesvirus, adenovirus, and vaccinia virus. These and other viruses have been investigated for their potential in viral oncolysis.7 Vaccinia is a DNA virus that replicates in the cytoplasm of the host cell during lytic replication and provides many of the advantages sought in an ideal oncolytic virus: large transgene capacity, excellent safety record (e.g., smallpox vaccination program), nonintegration into host genomes, and ability to infect a wide variety of cancer cells. In a previous phase I study, Park and colleagues administered JX-594 via intratumoral injection to 14 patients with primary or secondary liver tumors; they were able to define the maximum tolerated dose based on toxicity (hyperbilirubinemia) and observed three partial responses.8 In the above-mentioned recently completed trial published in Nature Medicine,1 Heo et al. randomly assigned 30 subjects with HCC to receive a direct image-guided intratumoral injection of 109 or 108 plaque-forming units of JX-594 distributed among up to five intrahepatic tumors on days 1, 15, and 29. Two-thirds of the study population had multiple tumors, and most had previously received some form of treatment. All but two subjects had well-preserved liver function. The treatment was well tolerated, with primary side effects referable to viremia: fevers, rigors, nausea, or emesis in a significant proportion of the subjects. One subject in each arm experienced hyperbilirubinemia. The primary radiographic end point was limited to evaluation at week 8, and, unfortunately, time to tumor progression (arguably an outcome that is most directly associated with the therapy under investigation) could not be assessed. The median overall survivals were 14.1 and 6.7 months for patients in the high-dose and low-dose cohorts, respectively. This difference is statistically significant and therefore provides the novel and exciting finding from the study. Heo et al. employed direct injection into the hepatic tumors. The primary advantage of direct injection lies in its delivery of a high dose directly into specific tumor(s). Importantly, this approach avoids the problem of inadequate delivery created by high tumor interstitial pressures that are known to reduce efficacy of intravascular delivery of therapeutic agents.9 However, intratumoral injection is subject to limitations when used to address multiple small tumors, let alone those that are clinically and radiographically unapparent. This potential limitation is diminished in the case of JX-594, based on the observation that high blood concentrations of viral genomes were detected just 15 minutes after intratumoral injection. In other words, “intratumoral injection” was ostensibly equivalent to systemic administration. Consequently, it is likely that even noninjected tumors received a direct dose of JX-594—an important point as it pertains to mechanism of action. Effects on radiographic assessments of tumor vascularity were observed in both injected and noninjected tumors. Although the authors posit that this suggests an immune-mediated response to tumors injected with JX-594, the systemic viral distribution described above probably contributed to direct viral infection and oncolysis of noninjected tumors, and thus probably contributed to observed effects on noninjected tumors. Humoral immunity against at least one HCC cell line in a panel of four was observed, and induction of cytotoxic T-cell activity against vaccinia peptides was also observed. But these measurements fall well short of definitive demonstration of immune-mediated cytotoxicity against autologous cancer. The authors appropriately suggest the importance of assaying direct cell-mediated cytotoxic effects against autologous tumor cells in future studies to determine whether the observed anticancer effects are truly due to immune effects rather than direct viral oncolysis. Ultimately, however, it may be reasonable to suggest that both mechanisms of action are needed. Initial phases of efficient oncolytic viral infection of tumor cells and robust replication with direct cytotoxicity are probably needed to release a sufficient number of tumor antigens that can be efficiently presented for secondary immune-mediated effects against the tumor. In our opinion, if the oncolytic virus does not initially replicate efficiently, it is unlikely that effective anticancer immunity will follow. Several other limitations of this otherwise excellent study should be underscored. First, using radiographic criteria, there were more responders in the low-dose group than in the high-dose group (67% vs. 57%). Thus, dose did not correlate with radiographic response and radiographic response did not correlate with survival. This remains unexplained. The authors discuss multiple mechanisms of action for JX-594. First, could it be that different doses led to different mechanisms of action being more operant, resulting in differences in outcome measures? Second, no information is provided on additional salvage treatments employed (e.g., chemoembolization) that may have influenced outcome and that perhaps contributed to the differences in overall survival. Third, both median survival figures for the high- and low-dose groups are well within ranges reported in phase II studies of other experimental HCC treatments.10 Finally, the evidence for in vivo vaccinia replication or amplification in this study may need some additional support in future trials: from blood samples taken from 30 subjects at seven time points, JX-594 was detected at just a single time point and in only 3 subjects. In conclusion, Heo and colleagues have performed a very important clinical trial of oncolytic viral therapy in a patient population in great need of discoveries and breakthroughs. The trial results suggest promise in the field, and it is hoped that future trials will confirm effectiveness and further elucidate mechanism of action. “Infectious” optimism is finally beginning to take hold for the future of oncolytic viral therapy and immunotherapy.