1. Therapeutic vaccination with defined tumor-specific antigens
Tumor cells carry antigens such as MAGE antigens that are absent from normal tissues, and that can be targeted by cytolytic T lymphocytes (CTL). Whilst it is possible to make such CTL recognize and kill autologous tumor cells in vitro, it is not known yet how to effectively induce CTL responses against tumor antigens in cancer patients that lead to tumor destruction.
In our clinical vaccination trials, patients with a MAGE-expressing cancer, often melanoma, are treated repeatedly with a MAGE vaccine.
Principle of anti-tumor vaccination with a defined antigen : The first step is to determine if the patient’s tumor cells express the tumor antigen. This can be determined by HLA typing, and by RT-PCR analysis of a tumor sample. Selected patients will receive repeated injections of a vaccine with the antigen. Usually this vaccine is a synthetic peptide, a recombinant protein, a recombinant virus coding for the antigen, or dendritic cells derived from the patient’s blood and forced to express this antigen. The effect of vaccinations on tumor progression is then assessed. Their immunogenicity is analyzed by comparing the frequency of anti-vaccine CTL in the pre and post-immune blood.
These trials have two main objectives. First, the effectiveness of various vaccination modalities can be assessed by following the clinical evolution of the tumor, by analyzing whether a specific CTL response to the vaccine antigen occurred, and by determining whether immunological and clinical responses are correlated. Secondly, these trials allow crucial biological material to be collected from vaccinated patients. Blood samples provide anti-tumoral CTL clones, which can be functionally characterized.
Different immunization modalities, such as immunization with peptides, or with the MAGE-3 recombinant protein, both with or without adjuvant, or with the ALVAC recombinant viral vector, have already been tried, they all are devoid of significant toxicity. A minority of vaccinated melanoma patients (about 10 to 20%) showed regression of metastatic lesions. This frequency is far beyond the reported incidence of spontaneous regressions of melanoma metastases, estimated at 0.2-0.3%, indicating that these regressions are linked to the vaccinations.
Example of a complete regression of cutaneous metastases in a melanoma patient after repeated vaccinations with MAGE-3.A1 peptide given without immunological adjuvant.
However, only 5% of the patients experience a true clinical benefit. Some of the remissions have lasted for several years. There is no evidence that one of the vaccines tested is more effective against the tumors than the others. CTL responses were detected in a minority of patients vaccinated either with peptides or with the ALVAC virus. These responses were often weak, and, in the case of the MAGE-3.A1 antigen, were observed mostly in patients who had tumor regressions.
The most likely explanation for the poor effectiveness of cancer vaccines observed until now is the fact that tumors have acquired the ability to resist destruction by antitumoral T cells, through unknown mechanisms (see « Analysis of T cell responses of vaccinated cancer patients » below). Future strategies aimed at improving cancer immunotherapy will undoubtedly rely on the characterization of these resistance mechanisms, which should define new important therapeutic targets. Vaccination at earlier stages, when the patient has no more detectable tumor after surgery but has a high risk of relapse, is another strategy that is being developed.
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