Selecting Target Antigens for Cancer Vaccine Development

Abstract

One of the principal goals of cancer immunotherapy is the development of efficient therapeutic cancer vaccines that are able to elicit an effector as well as memory T cell response specific to tumor antigens. In recent years, the attention has been focused on the personalization of cancer vaccines. However, the efficacy of therapeutic cancer vaccines is still disappointing despite the large number of vaccine strategies targeting different tumors that have been evaluated in recent years. While the preclinical data have frequently shown encouraging results, clinical trials have not provided satisfactory data to date. The main reason for such failures is the complexity of identifying specific target tumor antigens that should be unique or overexpressed only by the tumor cells compared to normal cells. Most of the tumor antigens included in cancer vaccines are non-mutated overexpressed self-antigens, eliciting mainly T cells with low-affinity T cell receptors (TCR) unable to mediate an effective anti-tumor response. In this review, the target tumor antigens employed in recent years in the development of therapeutic cancer vaccine strategies are described, along with potential new classes of tumor antigens such as the human endogenous retroviral elements (HERVs), unconventional antigens, and/or heteroclitic peptides.

Keywords: cancer vaccines; heteroclitic peptides; tumor antigens.

Figure 1

Schematic representation of different tumor antigens. Targets for tumor vaccines fall into tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs). TAAs are self-antigens that are either preferentially or abnormally expressed in tumor cells, but may be expressed at some level in normal cells as well. T cells that bind with high affinity to TAAs are low in number because they are deleted by central and peripheral tolerance mechanisms. Heteroclitic peptides are modified TAAs able to break tolerance and induce a more potent T cell response. TSAs include antigens encoded only by cancer cells and are truly tumor-specific, eliciting high-affinity T cells. Different colors indicate the difference between antigens presented by normal and tumor cells. The red-lines on T cells indicate more activated and tumor-specific cells.