Strategies for improving vaccines to elicit T cells to treat cancer

Abstract

Cancers have not evolved to be good vaccines. Indeed, most clinically evident cancers have escaped from the immune system. Thus, unlike most existing vaccines, one cannot simply mimic the disease agent to make a successful vaccine, but instead may need to combine several approaches. Our lab has developed a pushpull strategy in which we fi rst improve the immunogenicity of the antigens themselves by modifying the amino acid sequence to improve binding of epitopes to MHC molecules (a process called epitope enhancement). The next step is to “push” the response to improve not only the quantity but also the quality of the immune response, to achieve better avidity, longevity, and type of response, by using combinations of defi ned molecular adjuvants such as cytokines like IL-15, TLR ligands, and NKT cell agonist antigens. We and others have identifi ed synergistic combinations of these. Then, it is still necessary to overcome negative regulatory mechanisms that cancers elicit to suppress and evade the immune system. These include regulatory cells like Treg cells, myeloid-derived suppressor cells, M2-macrophages, regulatory type II NKT cells, and others, plus regulatory receptors on the T cells themselves such as CTLA-4 and PD-1, and regulatory cytokines like TGF-beta, IL-13 and IL-10. We call this the “pull” in vaccine strategy, removing the brakes to allow vaccine s to achieve their maximal potential. Here, we describe preclinical studies to examine each of these elements in cancer vaccines and clinical trials to translate these into patients, including an epitope-enhanced vaccine and blockade of TGF-beta. Overall, the combination of these strategies may allow more effective vaccines to treat established human cancers.