Open-label Phase II clinical trial in 75 patients with advanced hepatocellular carcinoma receiving daily dose of tableted liver cancer vaccine, hepcortespenlisimut-L
Marina G Tarakanovskaya, Jigjidsuren Chinburen, Purev Batchuluun, Chogsom Munkhzaya, Genden Purevsuren, Dorjiin Dandii, Tsogkhuu Hulan, Dandii Oyungerel, Galyna A Kutsyna, Alan A Reid, Vika Borisova, Allen I Bain, Vichai Jirathitikal, Aldar S Bourinbaiar, Marina G Tarakanovskaya, Jigjidsuren Chinburen, Purev Batchuluun, Chogsom Munkhzaya, Genden Purevsuren, Dorjiin Dandii, Tsogkhuu Hulan, Dandii Oyungerel, Galyna A Kutsyna, Alan A Reid, Vika Borisova, Allen I Bain, Vichai Jirathitikal, Aldar S Bourinbaiar
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
References
- Global Burden of Disease Cancer Collaboration. Fitzmaurice C, Dicker D, Pain A, et al. The Global Burden of Cancer 2013. JAMA Oncol. 2015;1(4):505–527.
- Alcorn T. Mongolia’s struggle with liver cancer. Lancet. 2011;377(9772):1139–1140.
- Jazag A, Puntsagdulam N, Chinburen J. Status quo of chronic liver diseases, including hepatocellular carcinoma, in Mongolia. Korean J Intern Med. 2012;27(2):121–127.
- Baatarkhuu O, Kim DY, Nymadawa P, et al. Clinical features and prognosis of hepatocellular carcinoma in Mongolia: a multicenter study. Hepatol Int. 2012;6(4):763–769.
- Baatarkhuu O, Kim DY, Bat-Ireedui P, Han KH. Current situation of hepatocellular carcinoma in Mongolia. Oncology. 2011;81(Suppl 1):148–151.
- Dondog B, Lise M, Dondov O, Baldandorj B, Franceschi S. Hepatitis B and C virus infections in hepatocellular carcinoma and cirrhosis in Mongolia. Eur J Cancer Prev. 2011;20(1):33–39.
- Sandagdorj T, Sanjaajamts E, Tudev U, Oyunchimeg D, Ochir C, Roder D. Cancer incidence and mortality in Mongolia - National Registry Data. Asian Pac J Cancer Prev. 2010;11(6):1509–1514.
- Oyunsuren T, Kurbanov F, Tanaka Y, et al. High frequency of hepatocellular carcinoma in Mongolia; association with mono-, or co-infection with hepatitis C, B, and delta viruses. J Med Virol. 2006;78(12):1688–1695.
- Oyunsuren T, Sanduijav R, Davaadorj D, Nansalmaa D. Hepatocellular carcinoma and its early detection by AFP testing in Mongolia. Asian Pac J Cancer Prev. 2006;7(3):460–462.
- Sun Z, Zhu Y, Xia J, et al. Status of and prospects for cancer vaccines against hepatocellular carcinoma in clinical trials. Biosci Trends. 2016;10(2):85–91.
- Sawada Y, Yoshikawa T, Ofuji K, et al. Phase II study of the GPC3-derived peptide vaccine as an adjuvant therapy for hepatocellular carcinoma patients. Oncoimmunology. 2016;5(5):e1129483.
- Butterfield LH, Economou JS, Gamblin TC, Geller DA. Alpha fetoprotein DNA prime and adenovirus boost immunization of two hepatocellular cancer patients. J Transl Med. 2014;12:86.
- Kuang M, Peng BG, Lu MD, et al. Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma. Clin Cancer Res. 2004;10(5):1574–1579.
- Takayama T, Sekine T, Makuuchi M, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000;356(9232):802–807.
- Abou-Alfa GK, Capanu M, O’Reilly EM, et al. A phase II study of cixutumumab (IMC-A12, NSC742460) in advanced hepatocellular carcinoma. J Hepatol. 2014;60(2):319–324.
- Breitbach CJ, Moon A, Burke J, et al. A Phase 2, open-label, randomized study of Pexa-Vec (JX-594) administered by intratumoral injection in patients with unresectable primary hepatocellular carcinoma. Methods Mol Biol. 2015;1317:343–357.
- Palmer DH, Midgley RS, Mirza N, et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology. 2009;49(1):124–132.
- Liu D, Staveley-O’Carroll KF, Li G. Immune-based therapy clinical trials in hepatocellular carcinoma. J Clin Cell Immunol. 2015;6(6) pii:376.
- Chen S, Li B, Xie H, et al. Phase I clinical trial of targeted therapy using 131I-Hepama-1 mAb in patients with hepatocellular carcinoma. Cancer Biother Radiopharm. 2004;19(5):589–600.
- Knox JJ, Qin R, Strosberg JR, et al. A phase II trial of bevacizumab plus temsirolimus in patients with advanced hepatocellular carcinoma. Invest New Drugs. 2015;33(1):241–246.
- Lee JH, Lee Y, Lee M, et al. A phase I/IIa study of adjuvant immunotherapy with tumour antigen-pulsed dendritic cells in patients with hepatocellular carcinoma. Br J Cancer. 2015;113(12):1666–1676.
- Batdelger D, Dandii D, Dahgwahdorj Y, et al. Clinical experience with therapeutic vaccines designed for patients with hepatitis. Curr Pharm Des. 2009;15(11):1159–1171.
- Batdelger D, Dandii D, Jirathitikal V, Bourinbaiar AS. Open label trial of therapeutic hepatitis B vaccine V-5 Immunitor (V5) delivered by oral route. Lett Drug Des Discov. 2007;4(8):540–544.
- Batdelger D, Dandii D, Jirathitikal V, Bourinbaiar AS. Open label trial of therapeutic immunization with oral V-5 Immunitor (V5) vaccine in patients with chronic hepatitis C. Vaccine. 2008;26:2733–2737.
- Arjanova OV, Prihoda ND, Yurchenko LV, et al. Phase 2 trial of V-5 Immunitor (V5) in patients with chronic hepatitis C co-infected with HIV and Mycobacterium tuberculosis. J Vaccines Vaccin. 2010;1:103.
- Tarakanovskaya MG, Chinburen J, Purevsuren G, et al. Immunotherapy of liver cancer with hepcortespenlisimut-L: open-label Phase II clinical study in patients with advanced HCC. J Immunother Cancer. 2015;3(Suppl 2):P200.
- Llovet JM, Ricci S, Mazzaferro V, et al. SHARP Investigators Study Group Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390.
- Llovet JM, Di Bisceglie AM, Bruix J, et al. Panel of Experts in HCC-Design Clinical Trials Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100(10):698–711.
- Morimoto Y, Tanaka Y, Itoh T, Yamamoto S, Mizuno H, Fushimi H. Spontaneous necrosis of hepatocellular carcinoma: a case report. Dig Surg. 2002;19(5):413–418.
- Stoelben E, Koch M, Hanke S, et al. Spontaneous regression of hepatocellular carcinoma confirmed by surgical specimen: report of two cases and review of the literature. Langenbecks Arch Surg. 1998;383(6):447–452.
- Okano A, Ohana M. Spontaneous regression of hepatocellular carcinoma: its imaging course leading to complete disappearance. Case Rep Oncol. 2015;8(1):94–100.
- Alqutub A, Peck D, Marotta P. Spontaneous regression of a large hepatocellular carcinoma: case report. Ger Med Sci. 2011;9:Doc07.
- Vora SR, Zheng H, Stadler ZK, Fuchs CS, Zhu AX. Serum alpha-fetoprotein response as a surrogate for clinical outcome in patients receiving systemic therapy for advanced hepatocellular carcinoma. Oncologist. 2009;14(7):717–725.
- Riaz A, Ryu RK, Kulik LM, et al. Alpha-fetoprotein response after locoregional therapy for hepatocellular carcinoma: oncologic marker of radiologic response, progression, and survival. J Clin Oncol. 2009;27(34):5734–5742.
- Shao YY, Lin ZZ, Hsu C, Shen YC, Hsu CH, Cheng AL. Early alpha-fetoprotein response predicts treatment efficacy of antiangiogenic systemic therapy in patients with advanced hepatocellular carcinoma. Cancer. 2010;116(19):4590–4596.
- Kuzuya T, Asahina Y, Tsuchiya K, et al. Early decrease in α-fetoprotein, but not des-γ-carboxy prothrombin, predicts sorafenib efficacy in patients with advanced hepatocellular carcinoma. Oncology. 2011;81(3–4):251–258.
- Yau T, Yao TJ, Chan P, et al. The significance of early alpha-fetoprotein level changes in predicting clinical and survival benefits in advanced hepatocellular carcinoma patients receiving sorafenib. Oncologist. 2011;16(9):1270–1279.
- Nakazawa T, Hidaka H, Takada J, et al. Early increase in α-fetoprotein for predicting unfavorable clinical outcomes in patients with advanced hepatocellular carcinoma treated with sorafenib. Eur J Gastroenterol Hepatol. 2013;25(6):683–689.
- Kawaoka T, Aikata H, Kan H, et al. Clinical outcome and prognostic factors of patients with hepatocellular carcinoma and extrahepatic metastasis treated with sorafenib. Hepatol Res. 2014;44(13):1320–1328.
- Lee S, Kim BK, Kim SU, et al. Early α-fetoprotein response predicts survival in patients with advanced hepatocellular carcinoma treated with sorafenib. J Hepatocell Carcinoma. 2015;2:39–47.
- Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–899.
- Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539–545.
- Silin DS, Lyubomska OV, Jirathitikal V, Bourinbaiar AS. Oral vaccination: where we are? Expert Opin Drug Deliv. 2007;4(4):323–340.
- Bourinbaiar AS, Mezentseva MV, Butov DA, et al. Immune approaches in tuberculosis therapy: a brief overview. Expert Rev Anti Infect Ther. 2012;10(3):381–389.
- Mapara MY, Sykes M. Tolerance and cancer: mechanisms of tumor evasion and strategies for breaking tolerance. J Clin Oncol. 2004;22(6):1136–1151.
- Gay N, Prasad V. Few people actually benefit from ‘breakthrough’ cancer immunotherapy. STAT. 2017. [Accessed March 8, 2017]. Available from
- Menis J, Litière S, Tryfonidis K, Golfinopoulos V. The European Organization for Research and Treatment of Cancer perspective on designing clinical trials with immune therapeutics. Ann Transl Med. 2016;4(14):267.
- Palucka AK, Coussens LM. The basis of oncoimmunology. Cell. 2016;164(6):1233–1247.
Source: PubMed