Vincenzo Cerundolo - Overview
Research in my 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. Our previous
studies 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 my 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). Our results indicate
that in vivo priming of melan-A–specific 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-A26/7–35–specific
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 maximize 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 us to develop in
my 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 my laboratory is focused on the analysis
of the mechanisms which control the processing and presentation of CTL
epitopes expressed within melanoma target proteins. We have 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. Our studies demonstrated
that pharmacological modulation of the proteasome’s 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.
