Melanoma Research
Melanoma Res. 2015 Oct; 25(5): 421–426.
Published online 2015 Sep 3. doi: 10.1097/CMR.0000000000000180
PMCID: PMC4560272
Adapted ECHO-7 virus Rigvir immunotherapy (oncolytic virotherapy) prolongs survival in melanoma patients after surgical excision of the tumour in a retrospective study
Simona Doniņa,a,b Ieva Strēle,c Guna Proboka,a Jurgis Auziņš,d Pēteris Alberts,
d Björn Jonsson,e,✠ Dite Venskus,d and Aina Mucenieced,✠
d Björn Jonsson,e,✠ Dite Venskus,d and Aina Mucenieced,✠Abstract
An
oncolytic, nonpathogenic ECHO-7 virus adapted for melanoma that has not
been genetically modified (Rigvir) is approved and registered for
virotherapy, an active and specific immunotherapy, in Latvia since 2004.
The present retrospective study was carried out to determine the
effectiveness of Rigvir in substage IB, IIA, IIB and IIC melanoma
patients on time to progression and overall survival. White patients (N=79)
who had undergone surgical excision of the primary melanoma tumour were
included in this study. All patients were free from disease after
surgery and classified into substages IB, IIA, IIB and IIC. Circulating
levels of clinical chemistry parameters were recorded. Survival was
analysed by Cox regression. Rigvir significantly (P<0.05)
prolonged survival in substage IB–IIC melanoma patients following
surgery compared with patients who were under observation (according to
current guidelines). The hazard ratio for patients under observation
versus treated with Rigvir was statistically significantly different:
hazard ratio 6.27 for all, 4.39 for substage IIA–IIB–IIC and 6.57 for
substage IIB–IIC patients. The follow-up period was not statistically
different between both treatment groups. These results indicate that the
patients treated with Rigvir had a 4.39–6.57-fold lower mortality than
those under observation. In this study, there was no untoward side
effect or discontinuation of Rigvir treatment. Safety assessment of
adverse events graded according to NCI CTCAE did not show any value
above grade 2 in Rigvir-treated patients. In conclusion, Rigvir
significantly prolongs survival in early-stage melanoma patients without
any side effect.
Keywords: ECHO-7 virus, immunomodulator, immunotherapy, melanoma, oncolytic, virotherapy
Introduction
Melanoma is one of the fastest-growing cancers and has the highest mortality rate of skin cancers 1–3. More than half of melanoma patients experience progression of the disease within 3 years of diagnosis 4,5. Current clinical practice guidelines for stage I–II melanoma provide few, if any, recommendations for treatment 6–9. The oncolytic property of viruses has been observed for over a century and is presently being studied intensively 10–16.
An oncolytic, nonpathogenic ECHO-7 virus, adapted and selected for
melanoma that has not been genetically modified (Rigvir), was approved
and registered in 2004 in Latvia for melanoma therapy 17–27.
The effect of viruses on cancers, including melanoma, has been tested
in clinical trials; however, the effectiveness of an approved and
marketed virus has not yet been shown in a clinical setting 12,14,16.
In
oncolytic virotherapy, Rigvir is a first-in-class. At a later time, a
genetically modified adenovirus was approved for head and neck cancer 28,29.
Melanoma is staged with substages from 0 to IV by measuring the
thickness of the tumour according to Breslow, by assessment of
ulceration, mitotic rate and metastases and by collecting pathologic
information on regional lymph nodes 30,31. On the basis of the stage of the disease, treatment is currently performed according to published guidelines 4,6–9.
The
aim of the present study is to test the effectiveness of Rigvir in a
retrospective study in substage IB, IIA, IIB and IIC melanoma patients
on time to progression and overall survival.
Methods
Retrospective clinical study patients
White patients (N=79)
who had undergone surgical excision of melanoma and diagnosis verified
histologically during the 4 years between January 2008 and December 2011
were included in this study. All patients were free of disease after
surgery and were classified into substages IB, IIA, IIB and IIC
according to the American Joint Committee on Cancer 30,31.
For disease progression, all were followed for a minimum of 3 months
until January 2014. The overall survival was checked on 5 June 2014 and
considered to reflect the status by 27 May 2014. The detailed study
population characteristics of this retrospective study are shown in
Table Table11.
Study population characteristics (N=79)
Current
guidelines for melanoma advise no treatment postsurgery for patients
who are classified into substages IB and IIA. Patients in substages IIB
and IIC are provided three options: participation in a clinical trial,
observation and interferon 7,8.
In the absence of strict guidelines, treatment with Rigvir was offered.
Thus, 52 study participants received Rigvir and 27 were observed
according to the guidelines. The patients who had been treated with
interferon were excluded from the present analysis as, in the registry,
they were too few to allow for any comparison.
As a part of the safety assessment, serum clinical chemistry parameters were recorded.
The
patients in this study were treated in the Latvian Oncology Center of
Riga Eastern Clinical University Hospital, the Latvian Virotherapy
Center in Riga and the Oncology Clinic of Piejūras Hospital in Liepāja,
Latvia.
The study was approved by the respective ethics committee.
Rigvir characteristics
Rigvir is a 2 ml frozen solution of an adapted and selected ECHO-7 virus strain, Picornaviridae family, Enterovirus
genus, Enteric Cytopathic Human Orphan (ECHO) type 7, group IV,
positive-sense single-stranded RNA virus produced under GMP. The titre
is not less than 106 TCID50/ml in sodium chloride for injection.
Method of Rigvir administration
Treatment
was started after surgical excision of the primary melanoma tumour when
the wound had healed. First, Rigvir (2 ml) was administered
intramuscularly regionally for 3 consecutive days. After about 4 weeks,
administration was repeated for three consecutive days and repeated
about 4 weeks later. Subsequently, a single administration of Rigvir
(2 ml, intramuscularly) was performed at monthly intervals during the
first year, at 6-week intervals during the first half of the second
year, at 2-month intervals during the second half of the second year and
at 3-month intervals in the third year. Rigvir is not to be used during
an acute infection.
Statistical analysis
Statistical
analysis of the data was carried out using the SPSS statistical
software, V.20 (SPSS Inc., Chicago, Illinois, USA). Mann–Whitney U-test and Wilcoxon tests (for continuous variables), Fisher’s exact test and the χ2-test
(for categorical variables) were used to test differences between and
within groups. Cox proportional hazard survival regression analysis was
carried out, which is the most commonly used multivariate model in
survival analysis. Thus, any difference between the groups, for example,
in age, has been taken into account in the Cox analysis. (This is in
contrast to Kaplan–Meier analysis, which is a bivariate analysis that
only takes into account one predictor at a time). Hazard ratios (HRs)
and 95% confidence intervals were calculated using bivariate and
multivariate Cox regression analysis on survival. Endpoints were
occurrence of metastases or disease recurrence for time to progression,
and death from any cause for analysis of overall survival. Predictors
(covariates) used in regression analysis were tumour stages, treatment
(Rigvir, observation), sex and age. A P value less than 0.05 from a two-sided test was established to indicate statistical significance.
Results
Effectiveness in patients: time to progression
Melanoma
patients of substages IB, IIA, IIB and IIC were studied according to
the postsurgery management that they had received. One group was treated
with Rigvir and the other was managed according to current guidelines
by observation (the control group is called ‘observation’) 6–9. The follow-up period was not statistically different between both treatment groups (Table (Table11).
Patients
who were free of melanoma after surgical excision and were treated with
Rigvir appeared to remain disease free (free of metastases and/or
recurrence) for a longer period of time compared with a similar group of
patients who did not receive Rigvir. The difference between the
treatment groups did not, however, reach statistical significance (Table
(Table22).
Regression estimates from Cox regression analysis of time to progression (N=79)
Effectiveness in patients: overall survival
The survival of patients who were treated with Rigvir was significantly (P<0.05) longer compared with a similar group of patients who did not receive Rigvir (Fig. (Fig.11 and Table Table3).3).
The difference between both treatment groups was statistically
significant on analysing all four substages together (IB, IIA, IIB, IIC)
(Table (Table3)3)
and on analysing stage II together (substages IIA, IIB, IIC). Adjusting
for patient age, sex and substage of disease, the HR was calculated in
multivariate Cox regression analysis. The HR for patients treated
according to current guidelines by observation versus treated with
Rigvir was 6.27 (P<0.005) for all patients, 4.39 (P<0.032) for substage IIA–IIC patients and 6.57 (P<0.014) for substage IIB–IIC patients (Fig. (Fig.1).1).
This indicates that the patients who were treated with Rigvir had a
4.39–6.57-fold lower mortality than those treated using current
guidelines by observation.
Cox regression analysis plots of survival of melanoma patients following surgery. P
is the statistical significance of the difference between the Rigvir
(—) group and the observation according to current guidelines
(observation) group (---) after ...
Regression estimates from Cox regression analysis of survival (N=79)
Safety assessment
In
the previous clinical studies, a few side effects were reported, for
example subfebrile temperature (37.5°C for a couple of days), pain in
the tumour area, sleepiness and diarrhoea. In this retrospective study,
however, there was no record of any untoward side effect from Rigvir
treatment or its discontinuation.
Serum clinical chemistry parameters were recorded and graded according to NCI CTCAE 32 (Table (Table4).4).
In the observation group, grade 1–3 values were obtained. All grade 3
samples were from two patients obtained within the last few months of
life. In one of these patients, progression of the disease was reported
simultaneously. In contrast, in the Rigvir-treated patients, values
above grade 2 were not observed.
Levels of serum clinical chemistry parameters during treatment
Discussion
Oncolytic
virotherapy is one of three forms of virotherapy (the other two being
viral vectors for gene therapy and viral immunotherapy, respectively).
Early observations of tumour regressions after virus infections have
been published starting from the late 19th century (cf. 10–16). Recently, several oncolytic viruses have been tested clinically 33–35 and Science named cancer immunotherapy the breakthrough of the year of 2013 36.
The melanoma adapted and selected ECHO-7 virus Rigvir is first-in-class
in oncolytic virotherapy; it is approved as therapy for melanoma.
The
present results show that in substage IB, IIA, IIB and IIC melanoma
patients, Rigvir administration after surgery significantly (P<0.05) prolongs survival compared with patients who were managed according to current published guidelines 6–9.
For the Rigvir-treated patients, the HR (risk of death) is
4.39–6.57-fold lower than for the control group treated according to
current guidelines by observation. The HR was calculated in multivariate
Cox regression analysis adjusting for patient age, sex and substage of
disease.
In this study, there was no record of any
untoward side effect from Rigvir treatment, which is in agreement with
clinical studies using other oncolytic viruses 14,16,33,34,37.
Moreover, no value higher than grade 2 was recorded in Rigvir-treated
patients. This is in contrast to most other cancer therapies, where
grades 3 and 4 are frequently observed (cf. 38).
Administration
of virus induces the formation of neutralising antibodies that might
potentially influence the efficiency of Rigvir. In previous studies, the
titre of neutralising antibodies against ECHO-7 was determined in both
healthy individuals and patients before administration of Rigvir. In 94
healthy adult participants tested, the titres were found to be low
(1 : 20 to 1 : 62) 39,40.
When tested in 155 adult cancer patients who had not been treated with
Rigvir, neutralising antibodies against ECHO-7 were detected in ∼50% of
the patients 41.
In a local study of 472 individuals, the presence of ECHO-7 antibodies
was shown to increase with age in children and level off to a plateau of
around 75% in adults 42.
To our knowledge, the prevalence of neutralising antibodies against the
ECHO-7 virus in the general adult population has not been reported.
Rigvir is an immunomodulator that affects both the humoral, antibody-mediated, and the cellular immune systems 20–22.
When virus adsorption and penetration to tumour tissue were measured,
it was shown that they are not influenced by the presence of
neutralising antibodies (titre 1 : 10) 43,44.
Furthermore, in a preliminary study, the levels of neutralising
antibodies to Rigvir during the first 18 months of treatment of melanoma
patients did not appear to correlate with time to progression after 3
years of follow-up 40. In that study, the neutralising antibody titre was 1 : 10 before the start of treatment (N=34).
After the first dose, the titre was 1 : 25 to 1 : 91 (determined
24–48 h after administration). A month later, before the second dose,
the titre was 1 : 250 to 1 : 320 (N=30); after the second dose,
it was 1 : 510 to 1 : 850. Two months later, before the third
administration, the titre was 1 : 160 to 1 : 895 (N=26) and after the eighth dose, 18 months after the first dose, it was 1 : 280 to 1 : 1350 40.
Also,
after intravenous administration, the correlation between antibody
titres varies from one virus to another, and neutralising antibodies do
not affect efficacy when local or regional administration is used 14,45,46.
An
estimated 14.1 million new cancer cases were diagnosed worldwide in
2012, the latest available. The number is expected to increase to 24
million by 2035. About 232 000 patients are estimated to be diagnosed
with melanoma in 2014 3. In the 20-year survival data analysis of the American Joint Committee on Cancer (cf. Figure 31.1 of 31), the majority of all melanoma patients belonged to stage I and stage II, 47 and 24%, respectively 31.
However, at present, clinical practice guidelines suggest postsurgery
therapy only for late-stage melanoma (radiation therapy and interferon
α) 6–9.
Rigvir has also been used in other types of cancer. In vitro, it reduces the viability of melanoma, as well as pulmonary, gastric, pancreatic, bone, and breast cancer cell cultures 47,48. It is oncolytic in melanoma and rectum cancer patients 49,50 (26, p. 115) and has been shown to improve the 5-year survival in rectum cancer patients 24.
Taken
together, the results suggest that a significant number of melanoma
patients would benefit from prolonging the survival with Rigvir
treatment. The results also show that this can be achieved without side
effects. Results suggest that Rigvir could also be tested in the
treatment of other types of cancer.
Conclusion
Rigvir
is an oncolytic, nonpathogenic ECHO-7 virus that significantly prolongs
survival in early-stage melanoma patients without any side effect.
Acknowledgements
The
authors are indebted to Anna Krilova, Oncology Clinic of Piejūras
Hospital, Liepāja, Latvia, for sharing patient information, and Oksana
Holodņuka, Riga Eastern Clinical University Hospital, and Linda Brokāne,
Latvian Virotherapy Center, for technical assistance, and Vaira
Saulīte, Institute of Microbiology and Virology, Riga Stradiņš
University, for expert advice.
Conflicts of interest
Aina
Muceniece, Dite Venskus, Jurgis Auziņš and Pēteris Alberts are past and
present employees of the Latvian Virotherapy Center. For the remaining
authors there are no conflicts of interest.
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