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| Research
Group |
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| Research
Interests |
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It
is now well established that cancer patients may acquire tumor specific
T- and B-cell immunity. Various types of human tumor cells often express
multiple CTL-defined tumor antigens that are shared among tumors, providing
the rationale for generic vaccines applicable to large subsets of cancer
patients. Our main interests are in understanding the dynamics of tumor
antigen-specific T cell responses and applying this knowledge to the design
of peptide-based therapeutic vaccines.
| Current Projects |
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Monitoring
antigen-specific CTL and helper T cell responses. Recently, we adopted
the fluorescent tetramer technology to visualize antigen-specific cells
directly by flow cytometry. We have enumerated and functionally characterized
single tumor antigen specific T cells in blood, metastatic nodes and tumor
masses from patients with metastatic melanoma as well as in blood from
healthy individuals. We identified a particularly abundant T cell repertoire
specific for the HLA-A2/Melan-A/MART-1 antigen, expressed in normal melanocytes
and melanoma cells, that is directly accessible to analysis by tetramers.
High frequencies of these T cells are detectable in single CD8+ human
thymocytes, in cord blood and the majority of HLA-A2 healthy individuals.
These T cells remain in a naïve functional state of differentiation
and undergo limited expansion in the periphery. A fraction of this repertoire
is activated in patients with melanoma and memory type T cells accumulate
at relatively high frequencies in metastatic lesions. We are currently
determining the functional potential of antigen-specific T cells freshly
recovered from tumors. We are also interested in setting up models to
understand the molecular mechanisms underlying the thymic selection of
high numbers of Melan-A/MART-1 tetramer+ lymphocytes. Efficient induction
of anti-tumor immunity requires the participation of helper T cells. Numerous
MHC class II-restricted tumor antigens have been recently identified mainly
in melanoma. We have recently started a project to use MHC class II tetramers
for the visualization of helper antigen specific T cells in melanoma.
Adoptive
transfer immunotherapy of cancer. Experimental evidence in mouse models
clearly show potent anti-tumor activity of adoptively transferred CTL.
Recent trials have also shown that antigen-specific CD8 T cells can be
safely transferred in humans but clinical efficacy remains limited. We
have started a project aiming at taking advantage of tetramer technology
to isolate high affinity tumor reactive T cells for adoptive transfer.
Currently, we are optimizing in vitro expansion protocols and means
of genetically engineering T cells to prolong their persistence in
vivo, and to address them to sites of tumor growth.
HLA-A2
trangenic mouse models for preclinical testing of cancer vaccines.
The most frequently expressed MHC class I allele in various ethnic
groups is HLA-A2. Transgenic mice carrying this allele lend themselves
to preclinical testing of peptide vaccines. We have recently found that
HLA-A2 tetramers can be used to monitor the anti-peptide CTL response
to vaccination in mouse blood, lymph nodes and spleen. Using this system
we observed that a combination of incomplete Freund's adjuvant and synthetic
oligodeoxynucleotides containing CpG motifs synergize in the induction
of a strong Melan-A/MART-1 peptide specific CTL response. We are generating
Melan-A/MART-1 knock out mice in the HLA-A2 transgenic background to study
the influence of central tolerance in the repertoire of Melan-A/MART-1
specific T cells.
Phase
I clinical trials of peptide vaccination in melanoma. Quantitative
monitoring of vaccine-induced tumor-specific CTL responses is a major
focus in our vaccination program. In collaboration with Daniel E. Speiser
and clinicians at the Multidisciplinary Oncology Center, University Hospital
of Lausanne (CHUV) we design and perform clinical trials in appropriately
selected patients with metastatic melanoma (see D.E.
Speiser's web page).
| Selected
publications |
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Miconnet, I., Koenig,
S., Speiser, D., Krieg, A., Guillaume, P., Cerottini, J.-C. and Romero,
P. 2002. CpG are efficient adjuvants for specific CTL induction against
tumor antigen-derived peptide. J. Immunol. 168:1212-1218.
Zippelius, A., Pittet,
M.J., Batard, P., Rufer, N., de Smedt, M., Guillaume, P., Ellefsen, K.,
Valmori, D., Liénard, D., Plum, J., MacDonald, H.R., Speiser, D.E.,
Cerottini, J.-C. and Romero, P. 2002. Thymic selection generates a large
T cell pool recognizing a self-peptide in humans. J. Exp. Med. 195:485-494.
Romero, P., Dunbar,
R., Valmori, D., Pittet, M., Ogg, G.S., Rimoldi, D., Chen, J.-L., Liénard,
D., Cerottini, J.-C. and Cerundolo, V. 1998. Ex-vivo staining of
metastatic lymph nodes by class I major histocompatibility complex tetramers
reveals high numbers of antigen-experienced tumor-specific cytolytic T
lymphocytes. J. Exp. Med. 188:1641-1650.
Romero, P., Pannetier,
C., Herman, J., Jongeneel, C.V., Cerottini, J.-C. and Coulie, P.G. 1995.
Multiple specificities in the repertoire of a melanoma patient's cytolytic
T lymphocytes directed against tumor antigen MAGE-1.A1. J. Exp. Med. 182:1019-1028.
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