Antigen-Specific Cancer Immunotherapeutics (ASCI)
The fact that the immune system of cancer patients is stimulated (primed) by the presence of the tumor, even though the resulting
immune response is insufficient to reject the tumor, has provided the basis for considering stimulation of the immune system
as a possible treatment against cancer.31 Several studies led to the identification of tumor-specific antigens and, in parallel, new approaches for activating or re-stimulating
the immune system were tested to induce a potent immune response.
This cancer immunotherapy approach is based on education of the immune system to fight cancer. It requires the appropriate
presentation of a tumor antigen by the antigen-presenting cells for the stimulation and expansion of tumor-specific T-cells.
Cancer immunotherapy comprises several types of treatments, including immunization but also modulation of immunity by cytokines
or antibodies. The immunization approach followed in antigen-specific cancer immunotherapeutics (ASCI) is aimed at eliciting
T-cell responses against tumor cells in a highly specific manner.32
The ASCI Concept
ASCI are a novel class of compounds aimed at treating cancer by targeting antigens that are selectively expressed by tumor
cells but not, or only at low levels, by normal cells. They are composed of a well-characterized tumor antigen in the form
of a recombinant protein, combined with an immunological adjuvant system. The use of recombinant proteins has several advantages
Advantages of Using Recombinant Proteins as Tumor Antigens
Despite the presence of tumor antigens on the surface of tumor cells, the immune system in most cases is not able to naturally
and spontaneously eradicate malignancy. The addition of adjuvant systems could result in directing the antigens against the
antigen-presenting cells (APC) and lead to a strong immune activation that could overcome the local tumoral immunosuppressive
processes. This would prove to be of major importance for the success of cancer immunotherapy because it could considerably
increase the proportion of patients showing clinical responses post-immunization. Following this hypothesis an immunological
adjuvant system has been selected for use in ASCI based on its ability to induce both high antibody and robust T-cell responses.
GSK Biologicals' lead tumor antigen for development of cancer immunotherapy is the MAGE-A3 tumor-specific antigen. This human
gene is silent in all normal tissues except the testis33 where there is no antigen presentation because of the lack of class I presenting molecules in the testis cells expressing
the gene.34 The MAGE-A3 protein is thus considered a truly tumor-specific antigen with expression in a variety of tumors such as melanoma,
NSCLC, bladder, and hepatocarcinoma.35
Two Phase 2 studies have been conducted in parallel using MAGE-A3. The first one has been performed in non-small cell lung
cancer (NSCLC) and provided the first sign of activity of the ASCI concept, with a 27% increase in the disease-free interval
compared to the control group when administered after complete resection of the tumor.36–37 The second Phase 2 study was carried out in metastatic melanoma with the aim of comparing two different adjuvant systems.
The study provided preliminary evidence of clinical activity and supported the choice of the most promising adjuvant system
for further clinical development.38 Additionally, the ASCI approach in these two studies showed side effects similar to those observed after classical anti-infective
vaccines. These preliminary safety and activity data have prompted to the initiation of Phase 3 trials in both NSCLC and melanoma
The principle of ASCI relies on the immunization of patients against their tumor antigens and has several expected advantages
summarized in Box 3.
Expected Advantages of the Antigen-Specific Cancer Immunotherapeutic (ASCI) Approach