Potent efficacy signals from systemically administered oncolytic herpes simplex virus (HSV1716) in hepatocellular carcinoma xenograft models

Our plain-English summary of Potent efficacy signals from systemically administered oncolytic herpes simplex virus (HSV1716) in hepatocellular carcinoma xenograft models, by L. Braidwood, K. Learmonth, A. Graham, et al (Journal of Hepatocellular Carcinoma, 2014).

The study

• Authors: L. Braidwood, K. Learmonth, A. Graham, J. Conner
• Journal: Journal of Hepatocellular Carcinoma
• Published: 2014;1:149-61
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Oncolytic herpes simplex virus (HSV1716), lacking the neurovirulence factor ICP34.5, has highly selective replication competence for cancer cells and has been used in clinical studies of glioma, melanoma, head and neck squamous cell carcinoma, pediatric non-central nervous system solid tumors, and malignant pleural mesothelioma. To date, 88 patients have received HSV1716 and the virus is well tolerated, with selective replication in tumor cells and no spread to surrounding normal tissue. We assessed the potential value of HSV1716 in preclinical studies with two human hepatocellular carcinoma cell lines, HuH7 and HepG2-luc. HSV1716 displayed excellent replication kinetics in vitro in HepG2-luc cells, a cell line engineered to express luciferase, and virus-mediated cell killing correlated with loss of light emissions from the cells. In vivo, the HepG2-luc cells readily formed light-emitting xenografts that were easily visualized by an in vivo imaging system and efficiently eliminated by HSV1716 oncolysis after intratumoral injection. HSV1716 also demonstrated strong efficacy signals in subcutaneous HuH7 xenografts in nude mice after intravenous administration of virus. In the HuH7 model, the intravenously injected virus replicated prolifically immediately after efficient tumor localization, resulting in highly significant reductions in tumor growth and enhanced survival. Our preclinical results demonstrate excellent tumor uptake of HSV1716, with prolific replication and potent oncolysis. These observations warrant a clinical study of HSV1716 in hepatocellular carcinoma.

In plain English

This was a preclinical study of the oncolytic herpes simplex virus HSV1716 (ICP34.5-deleted) in two human hepatocellular carcinoma cell lines, HuH7 and luciferase-expressing HepG2-luc, and in nude mouse xenografts. In culture, HSV1716 replicated at least as well as wild-type HSV-1 17+; in HuH7 at moi 0.001 it yielded 5,283 plus or minus 609 pfu per input virion versus 1,183 plus or minus 288 for the wild type (P=0.0001), with no significant difference at moi 0.01 (P=0.082). Virus killing of HepG2-luc cells gave an ED50 of moi 0.15 by light loss and 0.12 by MTT. In mice, permanent loss of light emission from HepG2-luc xenografts counted as a cure: four of six cleared after one intratumoral injection of 2x10^4 pfu and a fifth after a second injection on day 32; all 12 given 2x10^6 pfu cleared, versus none of 12 controls. Intravenous HSV1716 slowed HuH7 tumour growth and improved survival (log-rank P=0.0008 and P=0.0157 in two experiments), with high virus titres in tumours and almost none in other organs. The authors concluded the results support clinical translation of systemic HSV1716.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical study: in vitro virus replication and cell-killing assays plus subcutaneous xenograft experiments in nude mice
• Who was studied: Two human hepatocellular carcinoma cell lines (HuH7 and luciferase-expressing HepG2-luc; U87 glioma and one58 mesothelioma cells used for comparison) and female athymic nude mice bearing subcutaneous HuH7 or HepG2-luc xenografts (groups of 10 to 50 mice per experiment)
• Exposure: Oncolytic HSV1716 (and the luciferase-expressing variant HSV1716gCluc), compared with wild-type HSV-1 17+, given in vitro at various multiplicities of infection and in mice by intratumoral or intravenous (tail vein) injection at doses from 100 pfu to 1x10^7 pfu
• Main results:
  • In HuH7 cells at moi 0.001, HSV1716 produced about five-fold more progeny than wild-type HSV-1 17+ (5,283 plus or minus 609 versus 1,183 plus or minus 288 pfu per input virion, P=0.0001); at moi 0.01 the yields did not differ significantly (P=0.082)
  • In HepG2-luc cells at moi 0.01 after 72 hours, HSV1716 yielded 6,003 plus or minus 987 pfu per input virus versus 4,067 plus or minus 569 for HSV-1 17+ (P=0.0145)
  • HSV1716 ED50 in HepG2-luc cells was moi 0.15 by loss of light emission and moi 0.12 by MTT cell survival assay
  • Four of the six mice given a single intratumoral injection of 2x10^4 pfu HSV1716 had reduced luciferase levels by day 5
  • Of the two mice in that group still emitting light on day 32 and reinjected, one lost all light emission 12 days later (day 43), so five of the six were scored as cures
  • A cure in the HepG2-luc experiments was defined by light emission, not by pathological examination
  • All 12 mice given intratumoral 2x10^6 pfu HSV1716 showed reduced luciferase by day 12, with emissions at background by day 20; none of the 12 phosphate-buffered saline mice showed a reduction (groups significantly different, P less than 0.05 from day 16 onwards)
  • In the first HuH7 experiment (22 mice: 7 controls, 8 at 1x10^7 pfu, 7 at 1x10^6 pfu intravenously on days 1 and 4), both virus doses reduced tumour growth compared with controls (one-way ANOVA P less than 0.0001; P less than 0.001 for each dose), with no significant difference between doses
  • Survival was improved in both intravenously treated HuH7 groups compared with no-virus controls (log-rank P=0.0008); tumours were eradicated in four of 15 long-term survivors
  • In the second HuH7 experiment (17 mice given no virus, 1x10^5 or 1x10^6 pfu on days 1, 14 and 29), survival was improved (log-rank P=0.0157) and by day 66 four of six mice in the 1x10^6 pfu group and two of six in the 1x10^5 pfu group had no visible tumour
  • In biodistribution studies with HSV1716gCluc, virus was found at high titre in tumours, with only 1,000 pfu found transiently in the liver of one mouse (day 4) and the lungs of another (day 7), and no luciferase activity outside tumour extracts
  • After a single intravenous injection of 1x10^7 pfu HSV1716gCluc, tumour titres rose from 9x10^4 pfu/mL at 16 hours to 2.41x10^5 at 24 hours, 1.7x10^7 at 48 hours and 8.8x10^7 pfu/mL by 72 hours
  • In ten mice given escalating intravenous doses (100 pfu up to 1x10^6 pfu, two mice per dose), tumour titres at 72 hours exceeded the injected dose by at least ten-fold
• The authors' conclusion: The authors concluded that HSV1716 showed excellent tumour uptake, prolific replication and potent oncolysis in these two hepatocellular carcinoma models, and that the results support clinical translation of systemically administered HSV1716
• Limitations the authors state:
  • The authors said their proposed explanation for the better replication of HSV1716 than wild-type virus in these cells needs further work
  • The authors noted that light-emission monitoring depends on having luciferase-expressing cell lines
  • The authors declared that all of them are employees of the company developing the virus

Topics

Medical terms in this study, explained in our Lexicon: Carcinoma, Squamous Cell Carcinoma, Pleural Mesothelioma.

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