Breast Cancer Neoantigen Vaccination With Autologous Dendritic Cells

EXECUTIVE SUMMARY.

The achievements of personalized medicine in cancer research in developed countries make envision that various types of cancer in an advanced stage, will be in the medium term treatable diseases. The discovery of new therapies is the product of the achieved development of Translational Medicine (the laboratory findings translated in short term to the patient benefits), a new approach to applied medicine led by researchers in the universities in alliance with the private sector who carry out clinical studies. Despite the advances of Personalized and Translational Medicine in the developed world in Colombia, this discipline has an incipient development.

Due to its genetic instability, triple-negative breast cancer - (CMTN) (ER-, PR-, Her2 / neu-) among other tumors with a high number of mutations makes it resistant to chemotherapy/radiotherapy regimens generating high morbidity and mortality. Furthermore, genetic instability contributes not only to the immuno-editing of these tumors [5] but to the generation of a suppressive tumor microenvironment [6], which are factors that contribute to the escape of these tumors to their immunosurveillance [7, 8]. However, recent achievements suggest that these factors are controllable using personalized medicine. While immunosuppression is modulated with the use of anti-checkpoint antibodies ("anti-check points" such as anti-CTLA4, anti-PD1, and anti-PDL-1) [9], genetic instability that generates tumor neoantigens, may become the Achilles' heel of these tumors. Phase I clinical studies of patients with melanoma and lung cancer metastatic treated with Ipilimumab (anti-CTLA4 of anti-PD1) - to decrease immunosuppression - using together with vaccines peptides corresponding to tumor mutations that are presented in MHCI and MHCII molecules and are recognized by LT-CD8 as foreign antigens, led these cells to destroy the tumor efficiently when used as a vaccine [10-13]. For this reason, the identification of non-synonymous mutations of single amino acid and vaccination with 25 amino acid peptides incorporating these mutations (synthetic vaccines), is emerging as an alternative for cancer immunotherapy [10-13] in what is called neoantigen based synthetic cancer vaccines. In an approach that takes 16 weeks, today it is possible to go from the analysis of the tumor transcriptome to identify the universe of tumor mutations up to the vaccination of the patient with peptides containing tumor mutations, with the important clinical response to the tumor not achieved so far in patients with melanoma and non-small cell carcinoma of the metastatic lung [10-13]. Therefore, we propose to carry out the first clinical study in Colombia of vaccination of patients with CMTN using synthetic peptides that contain mutations of the tumor itself that will be presented by autologous dendritic cells in order to evaluate the immunogenicity and safety of this type of personalized vaccine. Achieving the specific objectives set out in this project will mean that we have validated in Colombia the experimental design necessary to identify unique epitopes in each tumor of the participants in the study in addition to demonstrating the safety and immunogenicity of these vaccines. Once this has been achieved, we consider having taken an important step towards implementation in our country of the use of this type of vaccine for immunotherapy not only of CMTN but of other highly fatal tumors such as glioblastoma, gastric, esophagus, and pancreas.

This project is carried out by the National University, the Hospital El Tunal de Bogotá, and the Fundación Salud de los Andes, has the collaboration of Professor Luis Fernando Niño and Andrés Pinzón, experts in bioinformatics in the Universidad Nacional; Dr. Chris Miller at Washington University at the McDonnell Genomic Institute at Washington University, School of Medicine in Saint Louis; has the advice of Dr. Pedro Romero from the University of Lausanne (Switzerland) who has extensive experience in immunotherapy clinical trials of melanoma patients with synthetic peptides as a vaccine and with researchers from the Research Group in Immunology and Clinical Oncology (GIIOC) of the Fundación Salud de los Andes.