Immunotherapy Analysis group
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The work of our group is aimed at understanding why some metastatic melanoma patients show tumor regression following vaccination whereas most patients do not. Recent results suggest that a local immunosuppressive environment at the tumor sites may be the main barrier to the efficacy of immunotherapy.
Study of the anti-vaccine and anti-tumoral T cell responses in melanoma patients vaccinated with an antigen encoded by gene MAGE-3.
When we initiated our attempts to vaccinate metastatic melanoma patients with tumor-specific antigens, our belief was that very strong cytolytic T lymphocyte (CTL) responses would be required for tumor regressions to occur. Ten years later, our immunotherapy trials can be summarized as follows. Only a small proportion of patients shows tumor regression : about 20% of the patients show some evidence of regression and about 6% of the patients show a level of tumor regression that can be considered to be clinically beneficial.
Most of the patients who regress do so despite a frequency of anti-vaccine T cells in the blood which is lower than 1/100,000 of CD8 T cells. This frequency is remarkably stable over several months. The anti-vaccine CTL are usually a single T cell clone, except when the patients are vaccinated with tumor antigens presented by dendritic cells. There the response is usually polyclonal, but it is noteworthy that the rate of tumor regression is not higher.
In patients vaccinated with a recombinant ALVAC virus coding for an antigen of gene MAGE-3, we observed that detectable anti-MAGE-3 CTL responses showed correlation with tumor regression. But the paradox remained that tumor regressions were observed in patients who made very low CTL responses against the vaccine.
The analysis of patient EB-81 vaccinated with ALVAC-MAGE-3 indicated that this patient had, in addition to a blood frequency of anti-MAGE-3 CTL of about 1/300,000, a hundredfold higher frequency of CTL directed against other tumor antigens. Moreover, these “anti-tumor” CTL were already present before vaccination. Similar findings were made with all the other patients who were analyzed. The antigens recognized by the anti-tumor CTL of patient EB-81 were identified. Most of these CTL recognized antigens encoded by gene MAGE-C.2, another gene belonging to the same family as MAGE-3.
To understand better what happened in the tumor, we used genetic approaches, namely PCR amplification of T cell receptor sequences, to evaluate the presence inside the metastases of patient EB-81 of the anti-vaccine CTL and of the main anti-MAGE-C2 CTL. The results were that the anti-vaccine CTL were barely enriched at the tumor sites relative to the blood whereas the anti-tumor CTL showed more than a hundredfold enrichment.
The results obtained in patient EB-81 have been completely confirmed in another patient treated with dendritic cells pulsed with a MAGE antigen.
These results led to a complete reversal of our views about the processes that lead to tumor regression. We now believe that as a melanoma evolves, there arises a spontaneous T cell response against specific tumor antigens. Thus, an immunosurveillance process occurs and probably results in the complete elimination of some tumors at an early stage. However, many tumors appear to escape this response. They manage to produce an immunosuppressive environment that renders ineffective the large number of T cells present in the tumor. A recent analysis of another patient indicates that the spontaneous T cell response against melanoma can occur at the stage of the primary tumor.
It appears that, in some vaccinated patients, a few anti-vaccine T cells manage to get a foothold in the tumor : they resist the local immunosuppressive conditions long enough to attack some tumor cells, and this results in a focal reversal of the immunosuppressive conditions. This in turn causes the restimulation and the proliferation of other anti-tumor T cells and it is these T cells that carry out the elimination of the bulk of the tumor cells (Fig.1). To summarize, the anti-vaccine T cells serve only as a “spark” that activates the regression of the tumor.
A result of this process is that the anti-vaccine T cells are also restimulated. Hence the correlation between regression and anti-vaccine T cell responses.
Our results also indicate that a new wave of naïve anti-tumoral T cells may be stimulated and amplified in the course of the tumor regression process.
In conclusion, we suspect that the difference between the patients who show tumor regression following vaccination and those who do not, is the “tightness” of the immunosuppressive conditions at the tumor sites. This tightness may vary from one metastatic site to another, explaining why in many vaccinated patients some metastases regress whereas others don’t.
- Study of the anti-vaccine and anti-tumoral T
cell responses in melanoma patients vaccinated with an
antigen encoded by gene MAGE-3
Thierry Boon, Aline Van Pel, Bernard Lethé and Christophe Lurquin
- Van Pel A, van der Bruggen P, Coulie PG, Brichard VG, Lethé B, van den Eynde B, Uyttenhove C, Renauld JC, Boon T. Genes coding for tumor antigens recognized by cytolytic T lymphocytes. Immunol Rev 1995;145:229-250.
- Coulie PG, Karanikas V, Colau D, Lurquin C, Landry C, Marchand M, Dorval T, Brichard VG, Boon T. A monoclonal cytolytic T-lymphocyte response observed in a melanoma patient vaccinated with a tumor-specific antigenic peptide encoded by gene MAGE-3. Proc Natl Acad Sci USA 2001;98:10290-10295.
- Karanikas V, Lurquin C, Colau D, van Baren N, De Smet C, Lethé B, Connerotte T, Corbière V, Demoitié MA, Liénard D, Dréno B, Velu T, Boon T, Coulie PG. Monoclonal anti-MAGE-3 CTL responses in melanoma patients displaying tumor regression after vaccination with a recombinant canarypox virus. J Immunol 2003;171:4898-4904.
- Coulie PG, Karanikas V, Lurquin C, Colau D, Connerotte T, Hanagiri T, Van Pel A, Lucas S, Godelaine D, Lonchay C, Marchand M, van Baren N, Boon T. Cytolytic T-cell responses of cancer patients vaccinated with a MAGE antigen. Immunol Rev 2002; 188:33-42.
- Godelaine D, Carrasco J, Lucas S, Karanikas V, Schuler-Thurner B, Coulie PG, Schuler G, Boon T, Van Pel A. Polyclonal cytolytic T lymphocyte responses observed in melanoma patients vaccinated with dendritic cells pulsed with a MAGE-3.A1 peptide. J Immunol 2003;171:4893-97.
- Germeau C, Ma W, Schiavetti F, Lurquin C, Henry E, Vigneron N, Brasseur F, Lethé B, De Plaen E, Velu T, Boon T, Coulie PG. High frequency of antitumor T cells in the blood of melanoma patients before and after vaccination with tumor antigens. J Exp Med 2005;201:241-248.
- Lurquin C, Lethe B, De Plaen E, Corbière V, Théate I, van baren N, Coulie PG, Boon T. Contrasting frequencies of antitumor and anti-vaccine T cells in metastases of a melanoma patient vaccinated with a MAGE tumor antigen. J Exp Med 2005;201(2):249-257.
- Boon T, Coulie PG, Van den Eynde BJ, van der Bruggen P. Human T cell responses against melanoma. Ann Rev Immunol 2006;24:175-208.