The Oncologic Investigation Center (CIO) located at the Institute with whom there is a cooperation agreement.
It has been assigned an area of 150 m2 devoted to the activity of the CIO. It conducted various research programs which can be found on the Main Menu.
The group’s work coordinated by Dr. Jose Mordoh has focused on the last fifteen years in the area of anti-tumor vaccines and mechanisms for evasion of the immune response. The approach that we proposed since then is the “translational reseach”, in other words, implementing a constant flow and bi-directionally between the findings derived from clinical research to basic research. The guiding principle of our group is trying to combat the tumor in the early stages, when the number of tumor cells and variety of mutations is lower.
It was a complex decision choose MELANOMA to begin implementing this strategy. The cutaneous melanoma resulting from the malignant transformation of epidermal melanocytes and its incidence continues to rise dramatically. It is considered the most aggressive of all skin tumor and their frequency in the population has increased in recent years, representing 3% of all malignancies.
The cutaneous melanoma continues to be a doctor’s challenge. According to the National Cancer Institute, the annual diagnosis of melanoma has increased by 619% and the annual mortality in a 165% in the period 1950-2000. In the United States, is fifth in the incidence of all cancers among men and in seventh place among women; is also the most common cancer in the group of women between 20 and 29 years of age. As with other tumors, the most important prognostic is the clinical stage of the disease. Patients with stage I-II are 40 to 100% survival at 5 years; in stage III, 30% and in stage IV, the average survival is 16 months, depending on the site of metastasis. Given the ineffectiveness of chemotherapy and the fact of being an immunogenic tumor, we decided to fight it using the immune system. As a center of this project we have developed anti-tumor vaccines and we started from two paradigms:
1) The first is that, since we do not know all the tumor Ags capable of triggering an immune reaction, there is a need to immunize all Ags available. For this we use tumor allogeneic irradiated cells.
2) The second is that in order to achieve effective action, the irradiated tumor cells must interact effectively with the dendritic cells (DCs) of the host. To achieve greater attraction of the DCs to the site vaccinal, we used GM-CSF, a powerfull chemoattractant of the DCs. Between October 2002 and January 2004, In Alexander Fleming Institute was conducted a Phase I trial with allogeneic vaccines and BCG as an adjunct in combination with GM-CSF or placebo. It vaccinated 20 patients with melanoma Stages IIB, III and IV, were free of disease after surgery (n = 16) or had minimal disease (n = 4). As a result of its low toxicity, and inducing a cellular immune response predominantly, conclusion suggest that the addition of 300-400 ug of GM-CSF allogeneic vaccines is useful to enhance the immune response in patients with melanoma. The 100% of the patients in stage IIB and 70% of stage III patients continuing disease-free four years post-surgery (1). Based on these results, will be implemented in Alexander Fleming Institute a clinical study of Phase II / III on 108 patients, that will last approximately three years.
Another approach to the paradigm above is making Dendritic Cells “fagociten” ex live apoptotic tumor cell and thus achieve better presentation of Ags, reaching in experimental systems effective preventive 80% against a challenge tumor (2.3). Based on the results above, pre-clinical studies were carried out in the CIO (4) and clinical at the Alexander Fleming Institute (5) using as a vaccine to DCs from patients with melanoma they have phagocytose apoptotic tumor cells of melanoma. These studies have shown that DCs can phagocytose cells of melanoma and present clones lymphocytes CD8-specific differentiation of the Ags MART – 1 and gp100, the antigenic peptides already produced six hours of phagocytosis.
In order to increase the potency of the immune system, we try to identify Ags expressed in stem cells expressed by various tumors. The main objective is to study the role of stem cells in the formation of melanoma and colorectal cancer (CRC), and if they are a target of the immune response.
This will propose the following objectives:
- Antigenic cell characterization with isolated clonogenic capacity from different human cell of melanoma and CRC:
– Study of oncogenes expression and Ags differentiation known.
– Finding new Ags for the characterization and isolation of item cell.
- Study of stem cells in human tumor samples to study its role in tumor formation.
Studies were also carried out genomics and proteomics on colon cancer. Our group has published the first work on DNA arrays in colon cancer in our country, in the CIO-FUCA (6). The overall objective in the long term is to quantify the expression and study the functional status of proteins present in different cell populations of tumor tissue of human cancer colon cancer, by combining the techniques of micro-Laser Dissection (MLD) and Inverted protein Microarrangements protein (IPM).
The proteomic approach will provide us with important information about the molecular mechanisms underlying the colorectal oncogenesis; this information will improve early diagnosis of tumors and reduce the chance that tumor cells metastatises with the potential to remain undetected. Specifically, this approach will allow us to characterize protein biomarkers, comply with the fundamental requirements for this role:
a) specific and mostly be specifically expressed in cancer cells with respect to normal;
b) Have high expression during all stages of tumor development;
c) Being on-expressed in the majority of tumor samples from different patients,
d) Finally, to facilitate their detection; these molecules would need to be expressed at the cell surface or secreted. The biomarkers can play a simple role of “fingerprints” useful for clinical diagnosis, or perhaps, constitute a potential therapeutic target. Therapies directed towards these molecular targets may be used in order to remove residual cells with metastatic potential or convert cancer into a chronic disease, it can be controlled over a very long period, perhaps using a biological therapies such as vaccines.