There’s a lot of interest in trying to enhance the host immune response and working on trying to see what we can do to make tumours that are not… The reason why cancers grow, really, is because, presumably in part, the host’s immune system is not recognising the tumour as foreign. So the idea of trying to enhance the host immune response against the tumour is longstanding and has been successful using a variety of antibodies in numerous solid tumours, including in breast cancer using pembrolizumab, for example, in the treatment of triple-negative breast cancer. In the early-stage setting the efficacy of pembrolizumab is independent of PD-L1 status, unlike in the metastatic setting where the tumour presumably, and by trials where there have been matched samples from early to late stage, has already downregulated immune markers on the tumour cells, making an immune response more challenging.

As a corollary to that, there has been longstanding interest in vaccines to try and enhance the host immune response. Of course, vaccines are stalwart for us in trying to prevent common infectious diseases that previous to vaccines had mortality. They’re based on setting up an immune response and a barrier to the infection being able to gain a foothold. So you basically have a sentry at the gate. That’s a little bit more difficult with cancers because there are many different kinds of cancers, even within the field of breast cancer, many different proteins expressed, different glycoproteins. So setting up a single vaccine against cancer per se hasn’t really panned out; we’re more trying to look at finding cancers earlier. But potentially if you started in the early-stage setting you could use vaccines as a way to enhance the host immune response and target the tumours that need more effective therapy.

So that’s a whole concept behind what we presented and there has been a lot of interest in vaccines for HER2+ disease where there is a known target so it makes it a little bit more straightforward. Just to show you the challenge in that, this research has been going on for decades and we now have an adjuvant trial, the FLAMINGO trial, looking at a vaccine in HER2+ high-risk disease, early-stage disease, that’s accruing patients, a phase III registration-based trial.

So it’s been a slow progress. There have been little bits of exciting information out there but nothing that yet has led us to an effective therapy. So we looked at a therapeutic cancer vaccine that’s based on a carbohydrate tumour antigen called globo H. This is linked to a carrier, keyhole limpet hemocyanin, which is a way to enhance the humoral response by deploying T-cells. Then there is an adjuvant that’s attached to this and vaccines use the concept of adjuvants to enhance the immune response against the antigen that is being presented. So we use OBI-821, which is a saponin-based adjuvant, to try and enhance this immune response.

We had previous data in the metastatic setting in triple-negative breast cancer that suggested that patients who mounted an immune response had an improved progression free survival compared to those who did not. It actually doubled the progression free survival with a hazard ratio of 0.52 in this initial phase II clinical trial. So we used data from other vaccine approaches that suggested that we really should be using vaccines in the early-stage setting because we know, again from matched tumour samples and from looking at humoral immunity, that the host immune response gradually decreases when you go from early- to late-stage disease with burden of disease and with prior treatment.

So we looked at patients with triple-negative breast cancer who express this antigen, so the carbohydrate tumour antigen globo H is highly expressed in triple-negative breast cancer. We randomised patients who had high-risk triple-negative disease to receive the vaccine, the OBI vaccine, so basically the globo H-based vaccine, with standard of care versus standard of care alone. Treatment was given over a course of two years because another thing we’ve learned about vaccines is that you can’t just do a vaccine, you have to keep amplifying the immune response following up. It’s important to keep in mind that patients in this setting will have recently received therapy that may have impacted their ability to respond to a vaccine. We give vaccines during chemotherapy for infections but we know that the host immune response is somewhat muted.

So we looked at invasive disease free survival in these patients and in order to qualify you had to have a tumour that expressed globo H and have a specific H score that was just moderate. We were able to enrol 575 patients in this trial internationally and we also had a very high Asian component, about 24%, but a number of other ethnic groups were included which is very helpful, with just over 50% classified as white. Then most patients were within a year from their breast cancer diagnosis, just under 12 months, and most patients, as you would expect, had infiltrating ductile cancer with a small number having medullary carcinoma and lobular carcinoma.

What we found in our interim analysis was that the trial met the futility endpoint. So the invasive disease free survival in the vaccine arm was not statistically different than in the standard of care arm. The invasive disease free survival rate at three years for the two groups was about 55% and similar was seen for overall survival.

I will say that overall the treatment was very well tolerated and people got toxicities from their standard of care chemo if they got capecitabine, but the issues that were associated with this trial really are facing many trials now, which is that pembrolizumab was introduced as a treatment which improved invasive disease free survival and improved overall survival most recently. That was only added onto the study much later because it wasn’t approved and, because this was an international study, many patients were not able to receive pembrolizumab. Now, the idea of vaccines is that we should be giving them with immune adjuncts like pembrolizumab and this may have helped to some degree. So only a minority of patients received those agents and that may have impacted the vaccine efficacy.

In addition, the amount of cancer that patients had at the time of entering the study, being eligible for the study, may have impacted the outcome with many of the patients having very poor response to their initial therapy.

Then we also had reviewed early on what patients received in the neoadjuvant setting in order to have residual disease at the time of surgery, which is one of the ways we were identifying high-risk patients. That also is quite variable around the world.

So we did terminate the study but I think it gave us important lessons and, of course, issues as treatments change rapidly for breast cancer, it’s very hard to incorporate all these treatments into the studies that have started some time before. So these are all important areas to consider as we develop these vaccine trials in the future. It’s certainly by no means the death of vaccine trials. We need to continue to move on and I think it’s likely that the first subtype that we will see benefit in is in HER2+ disease but, again, this is a rapidly changing field where there are more and more effective therapies being approved and put into clinical practice, most recently with trastuzumab deruxtecan being approved by the US FDA in both the neoadjuvant and adjuvant setting. So that we really are in a challenging situation where we start these trials, the standard of care changes during the trial to improve outcome and it’s not evenly distributed between the arms of the trial.

So there are challenges moving forward but I think that new vaccines, new approaches and combinations with these antibodies against PD-L1 or PD-1 may further enhance the immune effect. Being able to measure the immune activation may help us but the end is really going to be improving outcome and reducing recurrence in these patients.