I was asked to give a talk on understanding responses to cancer therapy: lessons learned from melanoma. So we’ve made tremendous advances in cancer therapy through the use of molecularly targeted therapy, also immunotherapy and melanoma is really a prime example. In the case of metastatic melanoma we now have over ten new regimens approved within the past five or six years for the treatment of patients with advanced disease. We, certainly as a group, have focussed on better understanding which patients are going to respond to therapy, which patients won’t respond to therapy and why and then strategies that we can actually use to make patients respond better.

So my laboratory has focussed on understanding therapeutic responses and what we’re starting to learn is that it’s not only the tumour itself but also the tumour microenvironment. Then we have a greater appreciation of the role of the immune system and also, interestingly, the environment and how the environment can actually influence cancer development and also how a cancer responds to therapy. One of the key features of that is actually the microbiome.

Yesterday I offered some insights into how the tumour genome and epigenome can actually influence therapeutic responses, how the tumour microenvironment can shape how a cancer develops and how it responds to therapy; also how the immune system can mould cancer responses. Then finally I really touched upon how the bacteria within our bodies can actually influence how patients respond to cancer therapy and it’s quite profound. So what we found, certainly other investigators have laid the foundation for this including Tom Gajewski from the University of Chicago and Laurence Zitvogel from Gustave Roussy have really in preclinical models really laid the groundwork that bacteria within the intestines of mice can actually modulate how cancers develop and how they respond to different forms of treatment like immune checkpoint blockade. So we wanted to understand if that was happening in patients and so we enrolled a large number of patients, now over 300 patients with metastatic cancer, in this case melanoma, who were undergoing treatment with systemic therapy and looked at the role of the microbiome and how they were responding to that cancer therapy. Interestingly found night and day differences between responders and non-responders with regard to both the diversity and the composition of the gut microbiome or bacteria that are actually sitting there in the intestine.

How far off are we from using bacteria pills to treat cancer?

Not far off. So certainly people are using faecal transplants to treat other diseases including Clostridium difficile; when patients get C. diff and they get superinfection you can actually give them back a normal microbiome and really cure them of their C. diff.  Faecal transplant is also being used in the context of inflammatory bowel disease and other diseases. The question is can we use it in the treatment of cancer and it’s a resounding yes. So we’re planning clinical trials where we actually use faecal transplant in conjunction with treatment with checkpoint blockade to see if we can actually enhance responses to checkpoint blockade. So that’s one form of how you can actually change the microbiome. Also can we create customised pills that contain components of the microbiome, both prebiotics and probiotics, to actually enhance cancer treatment? Again I think the answer will be yes but there are complexities that exist with that kind of a therapy. We’re certainly working on that with a number of other investigators worldwide; we’re also working with the Parker Institute for Cancer Immunotherapy on partnering up and really trying to find the best way to do this.

What is your take home message?

First we’ve made huge advances and we need to reflect on that and say we’ve come a long way but we still have a lot to learn. We have not cured cancer yet but we’ve made significant inroads. So what are the take home messages beyond that? We have to take on a more holistic approach to cancer therapy where we consider not only the tumour genome, epigenome, microenvironment, we also have to critically consider the role of the immune system in fighting cancer and then also the role of the environment, not only the microbiome but other environmental influences – diet, stress, things like that can actually influence how cancers develop and how they respond to different treatments. But a major component is that we really need to work together as a team globally to really advance, make the biggest advances in cancer therapy.

Could you tell us about your other abstract on microbiome research?

We had another talk yesterday where a graduate student in my laboratory, Vancheswaran Gopalakrishnan presented some of our data that had been previously presented at ASCO-SITC where he basically went over the results of our studies looking at patients with metastatic melanoma who were going on to treatment with immune checkpoint blockade and how we profiled both the oral and gut microbiomes. So he presented that data yesterday, again highlighting that there were no clear differences in the oral microbiome between responders and non-responders to therapy but there were very significant differences in the diversity and the composition of the gut microbiome in patients going on to PD-1 based therapy.
We also have another abstract that’s being presented by Dr Scott Woodman and that’s being presented on Tuesday where because we’ve made all these advances in patients with melanoma with late stage disease can we bring these advances to patients with earlier stage disease. So we know that over half of patients with melanoma have a mutation in a gene called BRAF and that you can actually target that mutation therapeutically by using BRAF and MEK inhibitors. Now, that’s been pretty successful in the treatment of stage 4 disease and so we asked the question can we bring that to patients with earlier stage disease. So we studied a cohort of patients with bulky stage 3 melanoma where they have melanoma that’s spread to the lymph nodes and if they had a BRAF mutation we did a study where they were either treated with conventional up-front surgery, which is the standard of care, versus treated with BRAF inhibitors before they were taken to surgery and then they got BRAF and MEK inhibitors after. Dr Woodman will be presenting those results tomorrow but they basically showed that for patients with metastatic melanoma that’s localised to the lymph nodes if they have a BRAF mutation and you treat them with a BRAF inhibitor before taking them to surgery, first, the risk of the disease coming back is significantly lower than if you had taken them straight on to surgery. Secondly, the treatment is associated with about a 58% of patients you don’t actually find any viable tumour at the time of surgery, meaning it’s highly effective when you treat them before surgery.

Then we found in the patients whose tumour didn’t completely go away we found mechanisms of resistance that could actually be targeted. So could you actually give someone additional medicine on top of the BRAF and MEK inhibitors to make the therapy more effective, either something like an ERK inhibitor or something like checkpoint blockade and make this form of therapy much more effective