The immune system functions not only to protect the organism against microbial infections but also to survey and control malignant neoplasms. Immune cells scan tissues with the objective of removing newly malignant cells before they turn into fully formed tumours. Harnessing the immune system to fight cancer has been explored for years with immunotherapy approaches employing a number of cytokines, engineered immune cells, antigens or even whole cancer cells as vaccines. Scientists from the EU-funded TLRPROSTATE project wished to generate and evaluate synthetic vaccines against prostate cancer using a different strategy. “Our idea was to chemically stimulate the toll-like receptors (TLRs) and therefore create an immune response,″ explains project coordinator Dr Juan Padrón. A novel approach to stimulating the immune system TLRs constitute a central constituent of the immune system as they are expressed on innate immune cells and help recognise the intruding pathogens. In particular, TLR4 recognises a wide array of ligands, including lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, responsible for macrophage activation and signal transduction. Intriguingly, recent evidence associates mutations in TLR4 with increased risk for prostate cancer. “We wanted to programme the TLR4 receptor so that it signals when it detects a prostate antigen,″ continues Dr Padrón and Dr. Pedro Miranda. In this context, scientists designed a bifunctional linker carrying a small molecule that binds an antigen on prostate cancer cells on one side and a weak agonist on the other side. The rationale was to trick macrophages into thinking that the prostate cancer cell is a bacterium and kill it. For this purpose, they designed the linker to target prostate specific membrane antigen (PSMA), a protein found to be overexpressed on the surface of the prostate cancer cells. To generate the linker, researchers successfully developed a new synthetic route that expedites the process and also allows reaction scaling-up. The overall vaccine synthesis process relies on simple purification techniques that allow production of up to 1 gram of compound. In addition, in vitro stability experiments were performed to validate the suitability of the linker for in vivo use, as well as efficacy assays to confirm linker binding to PSMA. The future of prostate vaccines Traditionally, prostate cancer is treated with pharmacological therapy but the majority of patients relapse and succumb to the disease. This clearly emphasises the need to discover novel therapeutic targets. The notable discovery of PSMA in recent years has opened up new avenues for the therapy of prostate cancer. The TLRPROSTATE molecule successfully matches PSMA and can activate TLR4 receptors, inducing an immune response. Although in vivo efficacy studies are pending, researchers are optimistic that “the synthetic vaccine will soon be tested in clinical trials.″ Anti-cancer vaccines have received great attention over the years with however, very little clinical success. Preventing the recurrence of potentially fatal diseases by stimulating the body’s own immune defence system is an ongoing task. Improved insight into how the immune system works will undoubtedly help find a cure for various types of cancer, saving millions of lives and reducing healthcare costs.
TLRPROSTATE, prostate cancer, vaccine, TLR4 receptor, PSMA