Darwin’s “Tree Of Life” Metaphor May Help To Beat Cancer

Any researcher who studies how cancer evolves within our bodies toward greater malignancy will tell you that the reason why curing cancer lies at, or beyond, the reach of modern medicine is because of tumor heterogeneity. In a direct comparison with Darwin’s “tree of life”, where all the species alive today are represented by the terminal twigs on a tree’s multiple branches, the development of cancer sub-clones is Darwinian evolution in miniature. From an original founding clone of cancer cells (the trunk) a branching structure of sub-clones fans out in space and time, throughout the tumor, each one different, having acquired its own unique set of mutations. Those mutations throw up corresponding new antigen proteins onto the cell surface so that researchers can commonly identify hundreds of these “neo” antigens, spread heterogeneously throughout the tumor. This startling heterogeneity bamboozles even ultra-modern immune therapy that uses monoclonal antibodies to target a tell-tale antigen protein marker on the surface of cancer cells and kill them. While these antibodies may initially be successful in driving cancer into remission, they frequently fail because their specificity for one of these neoantigens selectively targets only those sub-clones that bear it and selectively spares those that don’t. The surviving sub-clones quickly take over, resistant to the monoclonal antibody, the patient comes out of remission and rapidly goes downhill. The antigen “ecology” of the cancer cell surface is so complex it poses a real headache for cancer researchers. It reminds me of the old saying about someone who is so baffled by the complexity of the situation he finds himself in that “he can’t see the wood for the trees.” buy levaquin without prescription

However, in a new article in Science, an international group of cancer researchers led by Charlie Swanton and Nicky McGranahan, from the Crick Institute in London, together with Sergio Quezada from University College, London, have tried to make sense of all this antigen complexity. Swanton has previously branded cancer cells “hopeful monsters” because of their alarming ability, through mutation and chromosomal instability, to rapidly evolve resistance to the chemo we throw at them. But his team has just discovered that even rapidly evolving heterogeneous cancers – hopeful monsters – that have evolved so many differences they are barely comparable to the parent cancer clone, have an Achilles heel that could be exploited. buy zovirax without prescription

Not all antigens are the same. The team measured the activity of a range of immune system genes in lung adenocarcinomas that were relatively homogeneous, in that they had not evolved multiple genetically different sub-clones. They therefore had a high burden of antigens corresponding to the founding cancer clone – clonal antigens. They then compared these with forms of adenocarcinoma that were more heterogeneous, in that they had a much richer sub-clonal structure, and therefore a high burden of novel sub-clonal antigens and a lower burden of clonal antigens. They found eight genes that were more active in the homogeneous cancers, including PD-L1 (programmed cell death ligand 1) – an important checkpoint gene that reins in the T-cells of the immune system – and the gene for the inflammatory cytokine interleukin 6. These data, they said, suggested that a high clonal (trunk) antigen burden in lung adenocarcinoma is associated with an inflamed tumor microenvironment enriched with activated effector T-cells, held in check by inhibitory immune checkpoint molecules and their ligands. In a more detailed look at this immune phenomenon they clearly showed, in early stage lung cancer, that T-cells expressing high amounts of inhibitory PD-1 were far more prominent in more clonally homogeneous tumors. buy strattera without prescription

It is well known that tumors can hijack immune system checkpoint pathways, like PD-1, and use them to stop T-cells in their tracks and thus become resistant. For this reason, one promising line of immune cancer therapy involves treatment with monoclonal antibodies that blockade these checkpoint molecules. Prembrolizumab targets PD-1, but the team determined that it was far more effective in treating tumors that were low in sub-clonal antigens but had a high clonal mutation burden (all trunk and few branches). If the cancer had evolved into a rich sub-clonal structure involving high counts of sub-clonal antigens versus clonal antigens (rich branches but a thin trunk) patients respond poorly to treatment. For instance, one tumor sample they tracked, ZA6505, proved very resistant to prembrolizumab and patients, consequently, relapsed two months after treatment. It turned out that this was one of the most heterogenous cancers they had encountered with over 80% of its mutations classified as sub-clonal.

Could the opposite be true? Would they find T-cells capable of detecting clonal antigens in those patients in whom the checkpoint blockading drugs had proved more effective? An analysis of peripheral blood lymphocytes from a patient with a lung adenocarcinoma that had responded exceptionally well to prembrolizumab identified a T-cell population that recognized an antigen specific to a mutation in the HERC1 gene that had occurred early on in the life of the tumor, and was therefore a clonal antigen, but which was still present in all the ensuing sub-clones. It was therefore present in 100% of all the cells in the cancer. Exactly the same phenomenon repeated itself in melanoma samples.

The thrilling conclusion from all this is that the team have discovered that it is possible to see the wood for the trees. Tumors are capable of carrying the seeds of their own destruction. No matter how a tumor evolves, no matter how rich and variant its sub-clonal structure becomes, it is possible to identify trunk mutations – and their corresponding antigens – that survive clonal evolution and are still present – and therefore targetable – on all the cells in the cancer. Instead of producing monoclonal antibodies to target a chosen sub-clonal antigen – which can only attack some of the branches of the tumor – the answer to beating it may be to find these so-called trunk mutations and target these with dedicated T-cells.

What might their cancer therapy of the near-future look like? Once these trunk-attacking T-cells have been identified they could be removed from the patient’s body and bulked up in the laboratory before being injected back into the patient along with checkpoint blockading drugs like prembrolizumab, that stop the cancer restraining them, allowing them to let rip on the cancer. Or as Swanton’s team put it: “The identification of cytotoxic tumor-infiltrating T-cells recognizing clonal mutations, shared by all tumor cells, might hold promise for therapy strategies to address the challenges of tumour heterogeneity. The extensive clonal mutational repertoire present in smoking-associated non-small cell lung cancer could render this disease vulnerable to vaccination or T-cell therapies targeting multiple clonal antigens, in combination with appropriate immune checkpoint modulation.”

McGranahan, N., Furness, A. J. S., Rosenthal, R., Ramskov, S., Lyngaa, R., Saini, S. K., … Swanton, C. (2016). Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. http://doi.org/10.1126/science.aaf1490