At the World Vaccine Congress Europe event, Dr Philip Beer, a precision oncology specialist at the Wellcome Trust Sanger Institute, explained the evolution of cancer and discussed immunotherapy approaches.
DR Philip Beer, a precision oncology specialist at the Wellcome Trust Sanger Institute, addressed the World Vaccine Congress Europe 2018, which SciTech Europa Quarterly attended as the media partner. During his presentation, he discussed the scientific progress in understanding cancer and immunotherapy.
Beer’s experience includes genomic reconfiguration for NHS England, early oncology drug development, and his current academic research at the Sanger Centre and the ICGC.
Targeted therapies for cancer and immunotherapy
Beer began his speech by discussing the difference in treatment outcomes in targeted therapies for cancer and immunotherapy: “Targeted therapies in cancer do not result in long term remission for any patient…the results are often good, but they are always transient,” he revealed. By contrast, Beer argued that recent immunotherapy data he has seen shows that for approximately 10% of early-stage melanoma patients treated, the disease had gone away for at least ten years afterwards. He asked: “Can we use mechanisms of resistance to understand what those differences are and to learn more about how these therapies are working?”
Beer acknowledged the need to predict a response to immunotherapy not only for economic reasons, but also so that the patients get the right therapy.
The evolution of cancer and vaccination/treatment
Beer continued by comparing the evolution of cancer to that of Darwin’s evolutionary theory, stating: “The way we understand cancer at the moment is as an evolutionary process.” He then showed his audience a page from Darwin’s Origin of the Species, which illustrated how Darwin had perceived how species evolve – this is the famous image of apes progressing to the human, walking erect. He also highlighted the ‘tree of life’ and, indeed caricatures of Darwin with the body of an ape or monkey which symbolised evolution, demonstrating how some received his evolutionary theory.
Beer then compared the two former images to the thoughts put forward in recent research which sees the evolution of cancer in much the same way, before relating this to the targeting of tumour vaccines: “Cancer is clonal – it is initiated in a single cell – and we get a … very complex mix of different clones. The point at which we call this the most common ancestor is critical in cancer development; it is where you have a cell that contains a set of genomic events, a set of mutations, that are then present in all of the cells from this point going forward.”
Using this ideology of the ‘common ancestor’, Beer explained the evolution of cancer even further: “The set that has been created from the common ancestor does not change, however there may be reasons and there may be nuances that are not represented in terms of how cancer vaccines work in terms of uptake and spreading. I believe that you can make a fairly strong argument that if you are generating a patient-specific cancer vaccine, you have to be able to understand what is in all of the cells – what is in the trunk of the tree, rather than just the branches. You need to know this to be able to target every cell in the cancer.”
Beer then discussed parts of cancer growth and evolution with regards to genomic mutation: “There are three billion bases in the genome and assuming this process is roughly stochastic, by the time you have 1010 new cells in a tumour, you will have cells within that tumour that have every possible genomic mutation in the genome. 1010 cells is roughly one to two centimetres in diameter, it is a small tumour. What this means is that when the cancer presents, it is genomically saturated; it is comprised of clones that already have all possible mutations.”
Beer also commented: “An interesting aspect of immunotherapy and another difference with targeted therapy is when the selective pressure arises – with targeted therapy you only see the emergence of resistant clones when you apply that selective pressure; when you give the EGFR mutation in lung cancer you will then see the outgrowth of the T-790M clones, which were there all along but didn’t have any particular advantage. We hypothesise that the selective pressure will have already been there where the tumour presents.”
Parallel evolution in immunotherapy
Beer used several interesting analogies to explore the reasons why immunotherapy works. One of these was the analogy of agriculture to explain the parallel evolution in immunotherapy. He said: “It is known in agriculture that if you have a pest in a field, an aphid, and you use a chemical to try and wipe that out, then resistance is inevitable – you’ll always get bugs that acquire resistance to chemicals. The principles are the same for targeted therapy in cancer; you have enough of a reservoir of genetic diversity that there will be pre-existing resistance there.”
Tumour sequencing: the ICGC project
“A big problem with tumour sequencing approaches is low cellularity tumours, things like pancreatic cancer where you don’t have that many tumour cells, but you can gather other useful information by [lab] approaches to target the rearranged T-cell receptors, so you basically ask how many rearranged T-cells are there in the tumour and then begin to look at the clonality; and again there’s some emerging data about oligoclonality being associated with responses to immunotherapy,” he added.
Beer also spoke about his current research interest, which is in cancer assays. His team is trying to sequence tumours in a cost-efficient way. He added: “As part of this process we’ve built an immune module that pulls in all this kind of information that can potentially feed into better response and better understanding of why some patients respond and others don’t.” The immune module is the basis for a UK clinical trials network, which Beer says sponsors clinical trials at centres across the UK. It is also being used for collaborative projects with pharmacies and companies when they are looking for biomarkers within specific clinical trials.
His work in the International Cancer Genome Consortium is now entering its next phase. He concluded: “Glasgow is now the centre for the next phase of the ICGC project – the International Cancer Genome Consortium – the original project was to sequence 75,000 cancer genomes in an international collaboration where the tumour types were divided up between the countries. That is coming to an end, and the next phase is going to be focused on a more targeted look at the genes that we now know to be important in cancer.”