Title: Mutated neo-antigens in hepatocellular carcinoma
Luigi BUONAGURO (Italy) National cancer Institute "Pascale", Department of Experimental Oncology, Napoli
Danila VALMORI (France) INSERM U1102 "Cancer Vaccines and Immune Regulation" Institut de Cancerologie de l'Ouest-CLCC René Gauducheau, Saint Herblain
Bruno SANGRO (Spain) Department of Internal Medicine, Hepathology Unit, Universidad de Navarra, Pamplona, Navarra
Frederic AMANT (Belgium) Oncology Dept. University Hospitals Leuven - KU Leuven
Lucia LOPALCO (Italy) Division of Immunology, Transplantation and Infectious Diseases, Ospedale San Raffaele, Milano
Toivo MAIMETS (Estonia) Institute of Molecular and Cell Biology, Competence Centre for Cancer Reaserch, Tallin
Edvins MIKLASEVICS (Latvia) RSU Oncology Institute, Riga
Background and rationale: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Immunotherapeutic interventions may help at improving therapeutic outcome in HCC patients. Identification and immunological validation of specific mutated neo-antigens represents an essential knowledge.
Hypothesis: The hypothesis of the present proposal is that identification and immunological validation of mutated neo-antigens specific to HCC will be essential to subsequently develop immunotherapy strategies for improved clinical outcome in HCC patients.
Aims: The primary aim is the identification and immunological validation of mutated neo-antigens specific to HCC. Specific aims will be: 1) evaluate the mutational rate in HCC samples and predict the presentation of neo-epitopes by HLA-A2*01 allele; 2) assess the frequency of specific T cell response to such mutant epitopes in HCC patients, before and after treatment with checkpoint inhibitors (CI); 3) validate the immunogenicity of neo-epitopes in an HLA-transgenic mice and their therapeutic effect in a patient-derived xenograft (PDX) animal model; 4) identify mutated full-length proteins presented on the surface of HCC cancer cells; 5) develop MAbs to such mutated proteins and validate their specificity in vivo in a PDX animal model. Expected results and potential impact: The results of the proposed study will be the identification of HCC-specific target mutated neo-antigens (e.g. epitopes and proteins) and their immuological relevance in a PDX animal model and in HCC patients before and after CI treatment. Such results will have a potential extremely high impact, serving as a foundation for subsequent therapeutic strategies targeting HCC. Mutated neo-antigens will provide a source of immunogens to be used alone or in combination with wild-type antigens identified within the ongoing FP7-funded HEPAVAC project (Coordinator L. Buonaguro). The present HEPAMUT will complement and go far beyond HEPAVAC.
(Project selected for funding under JTC 2015)