Vincenzo Cerundolo Overview
Research in Professor Cerundolo's laboratory is focused on the understanding of the mechanisms which control the cell-cell interplay required for optimal expansion and activation of tumour-specific T cell populations. The use of HLA class I tetramers has provided important insights into the analysis of tumour specific immune responses, and allowed direct demonstration of expanded populations of activated tumour specific cytotoxic T lymphocytes (CTL) in some patients with metastatic melanoma. Amongst the known melanoma antigens recognised by CTL, melan-A or MART-1 is probably the best studied, and it has become an extremely useful target for immunotherapy. The previous studies of Professor Cerundolo and his team have established that in a significant proportion of A2 positive melanoma patients, CTL specific for the Melan-A epitope 26-35 can be detected ex vivo by tetramer staining. Results in their laboratory have demonstrated that the largest expansions of tumour-specific CTL is observed in tumour-infiltrated lymph nodes, where the CTL response can seem analogous to that seen in acute viral infections, with enormous frequencies of activated CTL specific for a single epitope (up to 1/8 of the CD8+ cells). The team's results indicate that in vivo priming of melan-Aspecific CTL is a late phenomenon, since only stage III or stage IV patients have an active immune response, while stage I/II patients and healthy volunteers have melan-A26/735specific CTL with functional and phenotypic markers of naíve population. If many melanoma patients are failing to prime and activate their melan-A specific CTL at earlier stages of their disease, then immunogens capable of priming in vivo these cells may be clinically helpful, as they will be able to recruit rapidly a large number of tumour specific CTL.
The main challenge for tumour immunotherapy is probably to jumpstart the CTL response at a far earlier stage of disease, to maximise the possibility for clinical impact. Powerful polyvalent immunogens capable of reliably priming tumour-specific CD8+ T lymphocytes are needed, and developing agents that are also simple to store and administer will greatly assist their wider use in early disease. This reasoning led the team to develop in the laboratory a recombinant defective vaccinia virus (MVA) encoding a string of 8 HLA-A2 and HLA-A1 melanoma peptides, which is currently used in a phase 1 clinical trial.
A second line of research in Professor Cerundolo's laboratory is focused on the analysis of the mechanisms which control the processing and presentation of CTL epitopes expressed within melanoma target proteins. The team has demonstrated that the MAGE-3 HLA-A2 (A2) epitope 271-279 is not efficiently generated by melanoma cells and that its poor presentation is due to the destruction of the epitope by the cytosolic protease proteasome. Their studies demonstrated that pharmacological modulation of the proteasomes proteolytic activities can relieve this block and result in an efficient killing of melanoma cells by CTL specific for the MAGE-3 epitope 271-279. Experiments are currently in progress to investigate further the mechanisms which control this antigen presentation block, as the understanding of these mechanisms is fundamental for a rational design of vaccine strategies aimed at boosting a CTL response specific for MAGE-3 protein.