Although various
immune checkpoint inhibitors (ICIs), used for the treatment of advanced
cancer, showed remarkably durable
tumor regression in a subset of patients, there are important limitations in a large group of non-responders, and the generation of novel immunogens capable of inducing protective cellular immune responses is a priority in
cancer immunotherapy field. During the last decades, several types of
vaccine immunogens have been used in numerous preclinical studies and clinical trials. However, although immunity to
tumor Ags can be elicited by most
vaccines tested, their clinical efficacy remains modest. Recently, we have developed an innovative
vaccine concept, called Variable
Epitope Libraries (VELs), with the purpose to exploit the high antigenic variability of many important pathogens and
tumor cells as starting points for the construction of a new class of
vaccine immunogens capable of inducing the largest possible repertoire of both B and T cells. In the present study, we decided to generate VEL immunogens derived from both classical and non-classical major histocompatibility complex (
MHC) class I molecules. The MHC molecules, responsible for antigen presentation and subsequent activation of T lymphocytes, undergo multiple modifications that directly affect their proper function, resulting in immune escape of
tumor cells. Two large VELs derived from multi-
epitope region of H2-Kd and Qa-2 sequences (46 and 34
amino acids long, respectively), along with their wild type counterparts have been generated as synthetic
peptides and tested in an aggressive 4T1 mouse model of
breast cancer. Significant inhibition of
tumor growth and the reduction of metastatic lesions in the lungs of immunized mice were observed. This study demonstrated for the first time the successful application of VELs carrying combinatorial libraries of
epitope variants derived from
MHC class I molecules as novel
vaccine immunogens.