Treating advanced melanoma with ipilimumab and HF10

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Published: 5 Jun 2017
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Prof Robert Andtbacka - Huntsman Cancer Institute, Salt Lake City, USA

Prof Andtbacka speaks with ecancer at ASCO 2017 about results from a phase II multicenter trial combining intralesionally injected HF10, an oncolytic Herpes virus, with anti-CTLA4 targeted therapy to treat metastatic or unresectable melanoma

He describes the encouraging response rates from the small trial group, with 41% overall response at 24 weeks, significantly more than trials using ipilimumab alone, with many patients experiencing a durable response.

Prof Andtbacka notes pending analysis of patients responses to assess if age and immune senescence may influence these outcomes, and highlights further trials testing HF10 alongside other immune agents, including a similar trial ongoing in Japan.

Intralesional oncolytic therapies were also discussed by Prof Sanjiv Agarwala at EADO 2017 .

 

HF10 is a herpes simplex virus that is not genetically modified but it lacks what’s called UL56 which is a neurovirulence factor. What that means is that when we inject this into patients who have either dermal subcutaneous or lymph node metastases for melanoma the patients don’t get a herpetic infection. However, what the HF10 does, it actually gets into tumour cells preferentially, it then replicates in the tumour cells, leaves the tumour cell lysis and exposure of tumour antigens to the immune system and activation of the immune system. We’ve shown in a phase I study that this can be quite effective in patients with squamous cell carcinoma of the head and neck as well as in melanoma. What we wanted to do in this study we really wanted to see if we could combine this with other therapies to get a more robust response in patients with melanoma. So as part of this in this study we combined HF10 with ipilimumab and ipimilumab is an anti-CTLA-4 antibody. The primary endpoint for this phase II study was the best overall response rate at 24 weeks. Specifically we were interested in both patients that had received prior therapies for their metastatic melanoma but also patients who were treatment naïve. We included patients that had stage 3b, 3c and stage 4 disease.

The primary endpoint for this study was met. We had 41% of patients at 24 weeks had an overall response and that was determined by immune related response criteria. We also followed patients subsequent to that and found that patients beyond 24 weeks, there were patients that had additional responses, up to 46% of patients having a response. That is, for us, very exciting because we know with ipilimumab by itself the response rate is between 15-19% in this patient population so adding this oncolytic immunotherapy, the oncolytic virus that we inject into the tumour, is quite exciting because we seem to be able to increase the response rate.

In terms of tolerability this was very well tolerated. Patients really did not have any substantial additional side effects compared to what we would see with ipilimumab by itself. Specifically there were no patients that stopped the therapy because of side effects to the HF10.

We also were interested in analysing patients who had had prior therapies versus being treatment naïve. Almost half the patients in this study had received prior therapies that they had progressed on. In those patients the response rate was 30% which is, for us, very exciting because often when patients progress on one therapy it’s difficult to get a response in subsequent therapies. In addition, patients who were treatment naïve the response rate was actually 50%. So this bodes well for future therapies in combining HF10 with ipilimumab but also other immune checkpoint inhibitors and take this forward in treating patients with metastatic melanoma.

You mentioned there injecting into the tumour so it was intralesional, not systemic?

Yes, we injected the HF10 intralesionally, into the tumour itself. These were injections into patients with dermal subcutaneous or lymph node metastases. I think it’s important to recognise also when we assess the response this was really the global response of the patients, not just the injected lesions that we assessed.

We have also done serial biopsies of these tumours to try to understand the mechanism of action and the immune activation that we see. Those analyses are now being performed and will be reported a bit later on.

You mentioned the patients being treated, I looked at the age data and there seemed to be quite a large variation. Do you think there might have been some better responders if they were young or older patients if their immune system reached a senescent stage that might affect outcomes?

We haven’t looked at that specifically. We had a broad age range of patients but the total study was 46 patients so it’s a little bit difficult to try to discern if the age makes a difference in terms of the response. We’ll be looking at these factors but we really need larger studies to further evaluate this and see if age makes a difference in terms of the immune activation and immune responses.

Finally, this was a combination with CTLA-4, are there any other planned combinations to try HF10 with or, say, SV10 with CTLA-4?

Yes. We actually are looking at doing the same, they are actually doing the same study in Japan right now, they’re combining HF10 with ipilimumab in patients with melanoma in Japan. That is quite interesting because we know that melanoma in Japan tends to be quite different compared to the melanoma that we see in the Western world. Most of the melanomas in the Western world are due to chronic sun exposure or chronic sun exposed areas whereas in Japan the majority of melanomas are really acral melanomas, so on the soles of the hand, soles of the feet, and also mucosal melanomas. Both of those melanomas tend to genetically be quite different compared to the chronically sun exposed melanomas. So it will be interesting to see the effect that this will have in the patients with acral melanomas.

We’re also looking at expanding this further to patients who have metastatic disease, specifically patients with lymph node and intransit metastases that we could surgically resect and use this in a neoadjuvant setting before we do the surgical resection, specifically combining this with a PD-1 inhibitor that we give HF10 plus the PD-1 inhibitor before surgery. Then three months later do the surgical resection and then continue with the PD-1 inhibitor in the adjuvant setting. All of this is really trying to activate the immune system before we do surgery to decrease the risk of recurrence of the tumour once we’ve done surgery.