Addressing Unmet Medical Needs Through Tailored Vaccine Design: The Importance of Adjuvant Systems - It is now possible to combine antigens with specific adjuvant systems to create more-effective vacc

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Addressing Unmet Medical Needs Through Tailored Vaccine Design: The Importance of Adjuvant Systems
It is now possible to combine antigens with specific adjuvant systems to create more-effective vaccines.


BioPharm International Supplements


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


Advantages of Using Recombinant Proteins as Tumor Antigens
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 (Box 2).

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 ( http://www.gsk-asci.com/).


Expected Advantages of the Antigen-Specific Cancer Immunotherapeutic (ASCI) Approach
The principle of ASCI relies on the immunization of patients against their tumor antigens and has several expected advantages summarized in Box 3.


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