Abstract
BackgroundAlpha fetoprotein (AFP) is an oncofetal antigen over-expressed by many hepatocellular cancers (HCC). We previously demonstrated that HLA-A2-restricted epitopes derived from AFP are immunogenic in vitro and in vivo despite high circulating levels of this oncofetal antigen. In order to test a more broadly applicable, HLA-unrestricted, inexpensive, cell-free vaccine platform capable of activating tumor antigen-specific CD8+ and CD4+ T cells, we tested full length AFP in a plasmid DNA construct in combination with an AFP-expressing replication-deficient adenovirus (AdV) in a prime-boost vaccine strategy.MethodsHCC patients who had an AFP+ tumor and previous treatment for HCC were screened and two patients received vaccination with three plasmid DNA injections followed by a single AdV injection, all delivered intramuscularly (i.m.).ResultsThe vaccine was well tolerated and safe. Both patients showed immunologic evidence of immunization. The first patient had a weak AFP-specific T cell response, a strong AdV-specific cellular response and recurred with an AFP-expressing HCC at nine months. The second patient developed a strong AFP-specific CD8+ and CD4+ cellular response and an AdV neutralizing antibody response, and recurred at 18 months without an increase in serum AFP.ConclusionsThe AFP DNA prime-AdV boost vaccine was safe and immunogenic. Circulating anti-AdV neutralizing antibodies at baseline did not prohibit the development of AFP-specific cellular immunity. The patient who developed CD8+ and CD4+ AFP-specific T cell immunity had more favorable progression-free survival. The observations with these two patients support development of this vaccine strategy in a larger clinical trial.Trial registrationClinicalTrials.gov: NCT00093548
Highlights
Hepatocellular carcinoma (HCC) is one of the most common cancers globally, with an incidence of over 600,000 new cases per year
Small, localized tumors are potentially curable with surgery, less than 20% of hepatocellular cancers (HCC) patients are eligible for these procedures because most patients have advanced disease at diagnosis or have liver dysfunction limiting aggressive treatment [5]
Patient 8 was free active disease but positive for cirrhosis, had normal Alpha fetoprotein (AFP) (5 ng/ml), had Karnofsky performance status 80%, was Child-Pugh A, HLA-A2+, and had intermediate detectable levels of anti-AdV neutralizing antibodies which were in the acceptable range for trial enrollment
Summary
Hepatocellular carcinoma (HCC) is one of the most common cancers globally, with an incidence of over 600,000 new cases per year. Small, localized tumors are potentially curable with surgery (resection and liver transplantation), less than 20% of HCC patients are eligible for these procedures because most patients have advanced disease at diagnosis or have liver dysfunction limiting aggressive treatment [5]. HCC is resistant to chemotherapy and other systemic treatment approaches. Alpha fetoprotein (AFP) is an oncofetal antigen over-expressed by many hepatocellular cancers (HCC). In order to test a more broadly applicable, HLA-unrestricted, inexpensive, cell-free vaccine platform capable of activating tumor antigen-specific CD8+ and CD4+ T cells, we tested full length AFP in a plasmid DNA construct in combination with an AFP-expressing replication-deficient adenovirus (AdV) in a prime-boost vaccine strategy. Methods: HCC patients who had an AFP+ tumor and previous treatment for HCC were screened and two patients received vaccination with three plasmid DNA injections followed by a single AdV injection, all delivered intramuscularly (i.m.)
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