Open-label Phase II clinical trial in 75 patients with advanced hepatocellular carcinoma receiving daily dose of tableted liver cancer vaccine, hepcortespenlisimut-L

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: allogeneic; immune tolerance; inflammation.

Conflict of interest statement

Disclosure AAR, VB, AIB, VJ, and ASB are officers for Immunitor. The other authors report no conflicts of interest in this work.

Figures

Figure 1

The distribution of patients according to duration of treatment between baseline and post-treatment AFP measurements. Vertical axis shows the absolute number of patients in each time category (X-axis). Median duration between first and consecutive AFP tests was 2 months (mean ± SD 2.75±2.45; 95% CI 2.2–3.3) Abbreviations: CI, confidence interval; SD, standard deviation.

Figure 2

Absolute number of HCC patients, as shown on Y-axis, followed up for 7–59 months (X-axis). The median follow-up time is 12 months (mean ± SD 15±9.7; range 7–59; 95% CI 12.8–17.2). Abbreviations: CI, confidence interval; HCC, hepatocellular carcinoma; SD, standard deviation.

Figure 3

Overall survival curve (solid line) of 75 HCC patients treated with hepcortespenlisimut-L as compared to survival of sorafenib-treated population (dotted line), based on tabulated data shown at the bottom of Figure 2 of published SHARP study over the same 12-month time frame. Y-axis shows percent of survival vs. horizontal axis corresponding to number of months on follow-up. The difference between 2 curves is statistically significant (P<0.001). Abbreviations: HCC, hepatocellular carcinoma; SHARP, Sorafenib Hepatocellular Carcinoma Assessment Randomized Protocol.

Figure 4

Increase in proportion of patients having lower levels of AFP after a median of 2 months, as shown in their absolute number plotted against Y-axis in relation to pre-set range of AFP plasma concentrations (shown on horizontal axis) into which they fall before (solid line) and after (dotted line) immunotherapy. Baseline median AFP level was 245.2 IU/mL (mean 4,233; range 7.2–92,407; 95% CI 1,186–7,280) and post-treatment value was 102.3 IU/mL (mean 2,539; range 0.9–54,478; 95% CI 503–4,575). There is a clear shift to the left toward lower concentrations of post-treatment AFP values compared to baseline distribution curve, which was statistically significant (R2=0.76; P=0.02). Abbreviations: AFP, alpha-fetoprotein; CI, confidence interval.

Figure 5

Plots expressed as percent (Y-axis) of baseline monthly values of AFP and bimonthly tumor size measurements by CT scan in patient #24 who had them evaluated for 7 months (X-axis). Changes in tumor burden were estimated by summing up perpendicular diameters of each lesion. AFP level in this patient was measured in ng/mL instead of usual units expressed in IU/mL. These values were converted into percentage figures relative to baseline values shown as 100% on Y-axis against X-axis showing number of months on follow-up. Linear regression analysis based on observed values shows strong dependency between these variables (R2=0.96; P=0.02) indicating that this relationship is unlikely to be random meaning that decrease in AFP was positively correlated with tumor burden reduction. Abbreviations: AFP, alpha-fetoprotein; CT, computed tomography.

Figure 6

Three consecutive abdominal CT scans of patient #24 carried out in June, August, and December 2014 as shown in three panels from left to right. When treatment initiated in July 2014, the patient had an AFP level of 47,937 ng/mL and 7 malignant lesions including thrombus in the portal vein, which recurred after ablation of 2 original primary tumors (12×11 and 11.1×10.4 cm in right lobe) in February 2014; in August 2014, after 3 weeks on V5, tumor sizes decreased by one third at which point AFP declined to 11,557 ng/mL. After 5 months on daily pill of hepcortespenlisimut-L, 4 out 7 lesions including thrombus cleared with remaining shrinking to under 1 cm at which time point AFP dropped down to 10.5 ng/mL—slightly above of what is considered the normal range between 0 and 8 ng/mL. Scans show planes with location of the largest lesion, which was later recognized as a cyst. By September 2016 all malignant lesions were cleared and AFP declined to 6.8 ng/mL. Abbreviations: AFP, alpha-fetoprotein; CT, computed tomography; Hepko-V5, hepcortespenlisimut-L.

Figure 7

Patient #63 started treatment in January 2015 (left panel); 3 weeks later, in February 2015 (right panel), both initially presented lesions shrank from 27.8 and 8.9 mm to 20.7 and 7.7 mm, respectively. Ascites clearly visible as dark gray band surrounding the liver at treatment initiation resolved after less than 1 month. After 5 months, AFP levels dropped from 5,034 to 48 IU/mL. Abbreviation: AFP, alpha-fetoprotein.

Figure 8

Transversal and coronal CT planes of patient #1 who presented with large (>5 cm) and small (A and B on the left). As patient was not eligible for resection due to proximity to portal vein, he consented to receive daily pill of V5. On the next visit, 4 months later, his AFP level dropped to 2.5 IU/mL at which time point lesions were cleared (C and D). Patient’s health improved remarkably; he gained weight, went back to work, and has remained in complete remission since then. Abbreviations: AFP, alpha-fetoprotein; CT, computed tomography; Hepko-V5, hepcortespenlisimut-L.

Figure 9

Patient #12 presented with single large tumor in September 2013 (shown in the left panel), which was removed surgically. In January 2014, multiple new lesions appeared in left lobe, which were not amenable to surgical intervention (panel in the center). At this time, his AFP concentration was extremely high (92,407 IU/mL)—no one in our entire cohort of 75 patients had more than that. In September 2014, the patient’s AFP levels reduced to 2.3 IU/mL and there were no visible lesions on CT scan (right panel). Between January and September, the patient received V5 intermittently for a total of 7 months. The patient is still alive and doing well. Abbreviations: AFP, alpha-fetoprotein; CT, computed tomography; Hepko-V5, hepcortespenlisimut-L.