"Hepatocellular carcinoma (HCC) is the most common primary liver cancer and accounts for about 6% of all new cancer cases worldwide. Given the lack of available effective treatments, the overall prognosis for HCC patients is poor, with a dismal 5-year survival of 5-6%. The main goal of this proposal is to develop a therapeutic cancer vaccine aiming at improving clinical outcome in early-stage HCC patients after loco-regional ablative therapy.HepaVac is an European consortium of academic, SME and pharmaceutical company partners with complementary and substantial expertise in cancer immunotherapy and vaccine development. The main objective of HepaVac is to develop a novel cancer vaccine approach for HCC based on epitopes naturally processed and presented by HLA class I and II (HLA-ligandome), to elicit both CD4+ T helper and CD8+ CTL tumor-specific effector and memory responses. The HCC HLA-ligandome will be identified in primary tumor tissues using a combined and integrated approach, developed and thoroughly validated by Partners #2 and #5. The selected peptide epitopes will constitute the candidate cancer vaccine for HCC, aiming at covering the broadest haplotype diversity with a multi-epitope and multi-TAA strategy. T cell epitopes derived from universal TAA and unique patient-specific mutated antigens will allow the design of a prime-boost vaccine strategy based either on a prime-boost schedule made of an “off-the-shelf” T cell epitope cocktail or on a schedule where the boost is complemented by a “personalized” T cell epitope cocktail. Both epitope cocktails will be adjuvanted in a novel and potent immunomodulator developed by Partner #6. Such a vaccination strategy will be tested in a randomized controlled multi-center phase I/II human clinical trial, assessing as primary endpoints safety and induction of specific cellular immune responses and, as secondary endpoints, OS and PFS of patients receiving the vaccine after tumor ablation vs tumor ablation alone."