We know that immunotherapies have been used for some time now but that generally speaking when used as single agents we don’t see the types of effects we want.

Most patients don’t respond, don’t have lasting tumour effects.

So the field is moving towards the combination of treatments.

We chose to target two different points within the cancer immunity cycle, both the presentation of antigens and the activation and priming of T-cells.

These two treatments, agonistic anti-CD40 monoclonal antibody and tremelimumab work in combination to activate T-cells to provide a tumour response.

The whole idea of the checkpoint blockade is to take the brakes off the immunity but you’ve been doing not only that but also putting the accelerator on as well.

You’re absolutely right.

We like to say that we’re stepping on the gas while cutting the brakes.

We hope that using these combinations, using these treatments together, will provide enough impetus to the immune system to overcome the immunosuppressive microenvironment of the tumour.

How much evidence was there that the anti-CD40 would do that – put on the accelerator?

We’ve been studying anti-CD40 for about a decade, both as a single agent and in combination with chemotherapy.

In each of those studies we’ve seen a response rate of somewhere between 20-25%.

Also we’ve seen activity in the serological biomarkers, specifically peripheral blood mononuclear cells we’ve seen evidence of immune activation, so we knew there was a signal there.

So we thought that when combining it with a CTLA4 antagonist like tremelimumab we may get more long-term responses.

So far that’s what we’ve seen.

Why tremelimumab and not ipilimumab, for example?

For practical reasons.

At the time of the study both agents were owned by Pfizer company and so it was a simple combination to make.

What did you do in the study, then?

We enrolled 24 patients and we treated them every twelve weeks with tremelimumab and every three weeks with agonistic anti-CD40 monoclonal antibody.

Patients tolerated the treatment well and, again, we had an overall response rate of 27%, which was very exciting.

27% overall response rate, what about survival?

The overall survival is 26.1 months with a progression free survival of only 3 months.

And this was a cohort of patients with metastatic melanoma. Anything else to say about them apart from that?

These patients were relatively heavily pre-treated; 70% of the patients had had previous treatment with a median of one treatment within the group and they did well.

This overall survival of 26.1, were there any within that who were living a lot longer?

Absolutely.

We have one patient in particular who is alive now three years after starting the study and she received no additional treatment.

We have seen patients who responded and then progressed on our trial go on to receive PD1 therapy and do extremely well.

So there seems to be a signal for the combination of these drugs with the PD1 blockade antibodies.

You were doing a double therapy, did that mean twice the toxicity?

No actually.

Surprisingly we saw very similar toxicities to what were seen in the single agent studies.

One thing that should be noted is that the threshold for toxicity was lowered a little bit in the tremelimumab.

So when tremelimumab was studied as a single agent the maximum tolerated dose was 15mg/kg IV every twelve weeks; in our study that threshold was lowered to 10mg/kg, however, the overall toxicity rate was very similar.

Of course, in the last few years we’ve heard pretty interesting results coming from ipilimumab, how do these compare, the results you’re getting here?

The results here are very favourable.

So, when compared to either ipilimumab as a single agent or tremelimumab, the addition of the CD40 agonist seems to really improve the overall response rate.

When you look back at the single agent tremi and ipi studies, the overall response rate was somewhere around 10%, now we’ve more than doubled that in this study.

What do you think doctors will be able to do with this in practical terms, then?

I think this combination hopefully will go on to see phase II and phase III studies take place.

I think we’ll be able to slot this alongside therapies like PD1 as part of our armamentarium against malignant melanoma and other malignancies.