Scientific Citations

An increasing number of studies is now devoted to immunotherapy of cancer. We evaluated the clinical benefit of hepcortespenlisimut-L (Hepko-V5 [formerly known as V5])—an oral therapeutic vaccine designated by the United States Food and Drug Administration (FDA) as an orphan drug for treatment of hepatocellular carcinoma (HCC). V5 was initially developed by us in 2002 to treat hepatitis B or C viral infections and liver cirrhosis. An increasing number of studies is now devoted to immunotherapy of cancer. We evaluated the clinical benefit of hepcortespenlisimut-L (Hepko-V5 [formerly known as V5])—an oral therapeutic vaccine designated by the United States Food and Drug Administration (FDA) as an orphan drug for treatment of hepatocellular carcinoma (HCC). V5 was initially developed by us in 2002 to treat hepatitis B or C viral infections and liver cirrhosis.

The outcome of open-label Phase II trial of daily dose of V5 pill was analyzed retrospectively.

Over a period of 5 years, 75 patients with advanced HCC were enrolled, consisting of 29 (38.7%) females and 46 (61.3%) males with a median age of 60 years (mean 61.6±8.1 years). Out of these, 23 (30.7%) had hepatitis B and 34 (45.3%) had hepatitis C infections, including 9(12%) with dual infection, 4 (5.3%) negative for both viruses, and 5 (6.7%) without established viral diagnosis. Most patients (94.7%) had underlying liver cirrhosis of varying severity.

After a median of 2 months of treatment, 50 out of 75 patients had experienced a decline in serum levels of the tumor marker, alpha-fetoprotein (AFP) (66.7%; P=0.006 by Wilcoxon signed rank test). Baseline median AFP levels were 245.2 IU/mL (mean 4,233; range 7.2–92,407; 95% confidence interval [CI] 1,186–7,280) and post-treatment values were 102.3 IU/mL (mean 2,539; range 0.9–54,478; 95% CI 503–4,575). The decrease in AFP was correlated either with tumor clearance or regression on computed tomography scans. The median overall survival time could not be established since 68 out of 75 (90.7%) patients were still alive after median follow-up of 12 months (mean 15±9.7; range 7–59; 95% CI 12.8–17.2). The first patient in this study received immunotherapy 5 years ago and still remains in complete remission. None of the patients experienced any serious adverse effects or toxicity.

The results indicate that hepcortespenlismut-L is a safe, effective, and fast-acting immunomodulatory intervention for HCC. The Phase III, randomized, double-blind, placebo-controlled trial is now initiated at the Mongolian National Cancer Center to confirm these promising findings.

We aimed to further investigate the role of hepcortespenlisimut-L (Hepko-V5 or V5), a new oral immunotherapy developed by us, for hepatocellular carcinoma (HCC) indication.

The interim data from ongoing Phase III placebo-controlled, randomized trial were evaluated on the initial group of patients in advanced stage of HCC with emphasis on liver function and tumor marker alpha-fetoprotein levels. Additionally, an in vitro study was undertaken to elucidate the mechanism of action of V5 by measuring with flow cytometry the expression of cytokines such as IL-2, INF-γ, and TNF-α and cell activation markers CD69 and Ki67 on CD4- and CD8-positive lymphocytes isolated from peripheral blood of healthy volunteers.

As early as one month after treatment initiation, there was a clear improvement in alanine transaminase, aspartate transaminase, alkaline phosphatase, and bilirubin levels among HCC patients who received daily dose of V5, but not in the placebo group. Additionally, alpha-fetoprotein (AFP) levels among V5 recipients decreased, while in the placebo group they rose. Clinical results are in line with in vitro observations indicating immune activation, as evidenced by many-fold enhancement of CD69, Ki67, and INF-γ expression and at the same time marked anti-inflammatory effect resulting in 10-fold decrease in TNF-α output and lack of influence on IL-2 production.

Hepcortespenlisimut-L, a tableted oral formulation derived from heat-inactivated pooled blood of patients with HCC and viral hepatitis shows beneficial clinical effect, as demonstrated by improvement in liver function and reduction of tumor marker AFP levels. These correlate with in vitro observations showing potent activation of the immune response and pronounced oral tolerance effect.

V-5 Immunitor (V5) has been evaluated in patients with chronic hepatitis C with concomitant HIV and Mycobacterium tuberculosis infections. Once-daily tablet of V5 was administered per os to 20 patients for one month. Every patient who entered the study had enlarged liver, elevated hepatic damage markers, which at the end of study have improved in 19 out 20 (95%) patients. The reduction was highly significant, from 1.72±0.34 to 0.18±0.28 μmol/ml•h (P=5.0 E-012) and 22.1±3.4 to 10.9±2.5 μM/L (P=5.7 E-009) for ALT and total bilirubin respectively.  Enlarged liver reduced from 3.5±1.4

to 0.95±1.1 cm above normal size (P=2.9 E-009). As patients were hospitalized in TB hospital they were treated with standard anti-TB therapy (ATT) in addition to V5. Surprisingly, V5 appeared to contribute to higher and faster than expected sputum conversion rate; 94.4% of smear-positive patients became negative within one month. TB-associated fever subsided within mean/median 4.1/3 days; indicators of inflammation such as elevated erythrocyte sedimentation rate and high leukocyte counts returned back to normal from 32.3±11.4 to 9.9±6.4mm/h (P=3.7 E-008) and 14.3±3.9 to 4.7±1.4x109L (P=7.1 E-010) respectively. Average body weight gain was 7.7 kg (P=4.6 E-007) and hemoglobin levels increased from 114±7.1 to 123.4±6.6 g/L (P=1.4 E-007). No adverse events were observed at any time. After one month 17 out of 20 patients were deemed cured from TB and discharged from the dispensary. Further studies are needed to confirm this preliminary observation suggesting that in addition to the beneficial effect in managing chronic hepatitis, V5 might also be useful as a safe and effective means for immunotherapy of tuberculosis.

Franciscan missionary Giovanni Di Plano Carpini traveled in 1245 to a country named Yeke Tartar, to visit a certain man called Genghis Khan. His journey’s report narrated peculiar dietary habits of the locals: “they eat anything, even lice”. Little that Carpini knew, he had actually documented the earliest known to us record of oral vaccination against blood-borne infections – an approach that is still used occasionally in the present-day Mongolia for therapy of hepatitis. Currently, efforts aimed at developing therapeutic hepatitis vaccines have switched to more palatable path, but we may still benefit from the insight of medieval Mongols. This review provides an update on development of hepatitis B and C vaccines as related to immunotherapy of hepatitis. Immunotherapy is a fast-moving field but the results so far failed to pitch woo. Current trends in research on therapeutic vaccine candidates and liver immunology are discussed. We subscribe to the idea that viral hepatitis is essentially an autoimmune disease generating immune-mediated liver damage.

Therapeutic vaccines need to be designed in such a way that self-destructive immunity of the host is targeted not the virus, which is not cytopathic.

We evaluated whether V-5 Immunitor (V5) tableted therapeutic bivalent vaccine comprising heat-inactivated HCV antigens from pooled blood of HBV- and HCV infected donors may produce clinical benefit through induction of oral tolerance and reduction of immune-mediated liver injury. Once daily dose of V5 was administered per os to 10 patients with chronic hepatitis C in an open-label study that lasted 1 month. Every patient who entered the study had elevated liver enzyme levels, which at the end of study have decreased in 100% of analyzed patients. The reduction was highly significant, from 157.7±73.4 to 49.9±43.8 U/L (P = 0.0013) and 147.0±79.2 to 58.7±56.6 U/L (P = 0.0132), for ALT and AST, respectively. The AST/ALT ratio has improved from 0.93 to 1.18 (P = 0.00058) indicating the reversion of progression to cirrhosis. None of intent-to-treat patients who were anti-HCV antibody positive at study entry, became negative after 1 month on V5 (P = 0.998). All patients, except one, reported complete recuperation from hepatitis C-associated clinical symptoms present at baseline (P = 0.0016) with Mantel Haenszel’s odds ratio 9.4 (P = 0.0021) at 95% confidence interval: 2.7 <OR < 476.3. No adverse events were observed at any time. The favorable biochemical and clinical responses have been observed in a small number of individuals for a limited time period. Larger scale and longer studies are needed to confirm our preliminary observations suggesting that V5 is safe and effective means for immunotherapy of chronic hepatitis C.

We evaluated whether V-5 Immunitor (V5) – tableted therapeutic bivalent vaccine comprising heat-inactivated HCV antigens from pooled blood of HBV- and HCV infected donors – may produce clinical benefit through induction of oral tolerance and reduction of immune-mediated liver injury. Once daily dose of V5 was administered per os to 10 patients with chronic hepatitis C in an open-label study that lasted 1 month. Every patient who entered the study had elevated liver enzyme levels, which at the end of study have decreased in 100% of analyzed patients. The reduction was highly significant, from 157.7 ± 73.4 to 49.9 ± 43.8 U/L (P = 0.0013) and 147.0 ± 79.2 to 58.7 ± 56.6 U/L (P = 0.0132), for ALT and AST, respectively. The AST/ALT ratio has improved from 0.93 to 1.18 (P = 0.00058) indicating the reversion of progression to cirrhosis. None of intent-to-treat patients who were anti-HCV antibody positive at study entry, became negative after 1 month on V5 (P = 0.998). All patients, except one, reported complete recuperation from hepatitis C-associated clinical symptoms present at baseline (P = 0.0016) with Mantel Haenszel's odds ratio 9.4 (P = 0.0021) at 95% confidence interval: 2.7 < OR < 476.3. No adverse events were observed at any time. The favorable biochemical and clinical responses have been observed in a small number of individuals for a limited time period. Larger scale and longer studies are needed to confirm our preliminary observations suggesting that V5 is safe and effective means for immunotherapy of chronic hepatitis C.