RESUMEN
The very impressive clinical results recently obtained in cancer patients treated with immune response checkpoint inhibitors boosted the interest in immunotherapy as a therapeutic choice in cancer treatment. However, these inhibitors require a pre-existing tumor specific immune response and the presence of tumor infiltrating T cells to be efficient. This immune response can be triggered by cancer vaccines. One of the main issues in tumor vaccination is the choice of the right antigen to target. All vaccines tested to date targeted tumor associated antigens (TAA) that are self-antigens and failed to show a clinical efficacy because of the immune self-tolerance to TAA. A new class of tumor antigens has recently been described, the neo-antigens that are created by point mutations of tumor expressing proteins and are recognized by the immune system as non-self. Neo-antigens exhibit two main properties: they are not involved in the immune self-tolerance process and are immunogenic. However, the majority of the neo-antigens are patient specific and their use as cancer vaccines requires their previous identification in each patient individualy that can be done only in highly specialized research centers. It is therefore evident that neo-antigens cannot be used for patient vaccination worldwide. This raises the question of whether we can find neo-antigen like vaccines, which would not be patient specific. In this review we show that optimized cryptic peptides from TAA are neo-antigen like peptides. Optimized cryptic peptides are recognized by the immune system as non-self because they target self-cryptic peptides that escape self-tolerance; in addition they are strongly immunogenic because their sequence is modified in order to enhance their affinity for the HLA molecule. The first vaccine based on the optimized cryptic peptide approach, Vx-001, which targets the widely expressed tumor antigen telomerase reverse transcriptase (TERT), has completed a large phase I clinical study and is currently being tested in a randomized phase II trial in non-small cell lung cancer (NSCLC) patients.
RESUMEN
Tumor Associated Antigens (TAAs) are the privileged targets of almost all the cancer vaccines tested to date. Unfortunately all these vaccines failed to show a clinical efficacy. The main reason for this failure is the immune tolerance to TAAs that are self-proteins expressed by normal and cancer cells. Self-tolerance to TAAs is directed against their dominant rather than against their cryptic epitopes. The best way to overcome self-tolerance to TAAs would therefore be to target their cryptic epitopes. However, because of their low HLA-I affinity, cryptic peptides are non-immunogenic and cannot be used to stimulate an antitumor immune response unless their immunogenicity has been previously enhanced. In this paper we describe a general approach to enhance immunogenicity of almost all the HLA-B*0702 restricted cryptic peptides derived from TAAs. It consists in substituting residues at position 1 or 9 of low HLA-B*0702 affinity cryptic peptides by an Alanine or a Leucine respectively. These substitutions increase affinity of peptides for HLA-B*0702. These optimized cryptic peptides are strongly immunogenic and very importantly CTL they stimulate recognize their native counterparts.TAAs derived optimized cryptic peptides can be considered as universal antitumor vaccine since they escape self-tolerance, are immunogenic and are not patient specific.