WCCS 2016

Oncolytic virotherapy in the treatment of melanoma

Dr Robert Andtbacka - Huntsman Cancer Institute, Salt Lake City, USA

I’ve had several talks, I’ve had four talks. In the first talk we talked about an update on the OPTiM study which was a phase III randomised clinical trial in which T-Vec also known as talimogene laherparepvec was used to treat patients with unresectable stage 3 and 4 melanoma. Specifically what we looked at in this update was the patients with earlier disease, those patients with stage 3b, 3c  and stage 4 M1a disease and we were interested in looking at patients who responded to T-Vec, specifically the patterns of response. We know with immunotherapy it’s not uncommon for patients to have progression of their disease before they respond and we always wonder does that affect then the longevity of the response and durability of the response. And what we found in these patients who were treated with T-Vec, first of all, the response rate to T-Vec and the durable response rate to T-Vec was seen in 25% of patients. We also found that about half of these patients actually had progression prior to response. The majority of the patients who progressed had new lesions that developed but we found that the time for them to develop a response was 5.1 months which is about two months longer compared to patients who did not progress prior to responding. But even if they had this progression prior to response it did not appear to affect the durability of the response. Actually at the data cut-off over 80% of patients are still responding in both the ones who progressed and the ones who did not progress, prior to developing a response. In addition it also has not affected the overall survival. The median survival for these patients had not yet been reached just because the majority have not progressed yet. So that’s very encouraging and especially from a clinical perspective, it really guides clinicians that if you treat patients with T-Vec, even if the patients progress, continue treating because there is a good likelihood that the patients will respond unless the progression that the patient experiences is clinically significant that would then warrant the use of other therapies for the patient.

What are your thoughts on oncolytic virotherapy?

For patients who are treated with oncolytic virotherapies the side effects generally are truly minimal, the majority of the side effects are grade 1 and grade 2 toxicities. There are very few grade 3 or greater toxicities in patients treated with T-Vec. The most common grade 3 or greater toxicities are a bit of discomfort at the injection site and also a bit of cellulitis over the injection site but this is seen in around 2% of patients so a very small number. Otherwise the treatments are extremely well tolerated. My clinical experience with using T-Vec for many patients is that patients can have a bit of fatigue, they can have a bit of shakes and chills at the initiation of their therapy. We also know that that tends to be transient and as they receive more injections of T-Vec the incidence of those shakes and chills gets less and less so usually by the fifth or sixth treatment very few patients have those side effects. Overall extremely well tolerated and I think this is again encouraging for patients because it really does not affect their quality of life and allows them to really go about with their daily activities. Other oncololytic immunotherapies really seem to be very similar to this that they have very few grade 3 and greater toxicities.

What other results have been discussed at this meeting?

At the meeting we also did discuss some results of another study that we are doing. We know for patients who have metastatic melanoma that the oncolytic virotherapies worked the best in patients with earlier disease.  These are patients that have in-transit lesions, macroscopic lymph nodes, these are the 3b and 3c patients and also patients who have distant disease to subcutaneous areas and lymph nodes respond the best. Patients who have metastases to the lungs, and metastases to the liver really don’t seem to respond as well for this in monotherapy. Similar to what we are doing with all other therapies in cancer we really are looking at combinations for these patients with more advanced disease. And we have combined oncolytic immunotherapies with checkpoint inhibitors and one of those combinations is using HF10 which is also an oncolytic immunotherapy. It’s a herpes simplex type 1 therapy that we have combined with ipilimumab in patients with unresectable metastatic melanoma. When we combine that, first of all we have found that there really is no added toxicity by combining that oncolytic virus with ipilimumab. And the majority of the toxicity or the side effects that we see really comes from the ipilimumab and there’s no dose limiting toxicity. Secondly, we found that the response rate that we see appears to be greater with the combination than with either agent as single agents. Specifically in patients who have had no prior therapy and receive this as their first line therapy the response rate is over 50%, about 58%, and the disease control rate is around 70% so this works very well for patients. Now patients who have received prior therapy often can be very challenging to treat specifically patients who have failed other therapy such as PD-1 inhibitors and also BRAF MEK combinations can be quite challenging to treat. In this study we have had about almost half of the patients had failed prior therapies before they went on HF10 plus ipilimumab and what we found was that 40% of those patients actually responded to the therapy which is again encouraging that we can use these oncolytic viruses to change the response rate and potentially to change the tumour microenvironment to make tumours more responsive so some of the checkpoint inhibitors.

Additionally what we have about talked also is in patients that have been on prior therapies with PD-1 inhibitors and anti-CTLA-4 therapy with ipilimumab and have not responded to this. When we do biopsies of those lesions in the patients we often find that there are no, or very few, tumour infiltrating lymphocytes and really for those patients to respond or for those lesions to respond they need to have those lymphocytes in there need to have correct lymphocytes in there.  What we’ve done is we have used these oncolytic immunotherapies to then inject those lesions and then look at the change in the tumour microenvironment and it appears that these oncolytic immunotherapies are very good at then bringing in the immune cells, specifically CDA positive T cells that will potentially then make the patient more responsive to the checkpoint inhibitors. We have also found that when we then treat them with these oncolytic virotherapies that depending on the type of T cells, or immune cells, that come in and the proteins that they express we seem to be able to distinguish between the patients who will and will not respond. This is still early work but very encouraging. We now may have mechanisms to affect the tumour microenvironment to make therapies work better and we also may be able to have markers in those tumours to try to determine who will and will not respond to the therapies.

Where do you see this therapy heading in the near future?

We are only seeing the beginning of the use of oncolytic viral immunotherapies so I think that they have roles in multiple levels. I think that there is a substantial role for these therapies as monotherapies and we know that especially in patients with earlier disease these therapies can have very robust responses in patients and with over 50% of patients responding. They can also do this with very limited toxicity. In patients with more advance disease I think we need to think about combination therapies. One of the advantages of these oncolytic immunotherapies is that when we combine them with other therapies they don’t seem to increase the toxicity profile for the patients. Thirdly I think that these oncolytic immunotherapies also have the ability to change the tumour microenvironment and make other therapies work better. So I think that they really work in multiple levels of trying to affect the immune system and activate the immune system.

A fourth thing that we are looking at as well is to use these oncolytic immunotherapies in patients with resectable disease. We know patients that have reoccurrence of their disease in melanoma in the form of in-transit disease or lymph node reoccurrence. If we can surgically take that out we would recommend that that is the current standard of care but when we do that there is a large number of patients that will reoccur. And the question is what can we do to try to prevent those patients from reoccurring? There is some initial data saying that using these oncolytic immunotherapies we can prevent patients from developing distant disease. We are now using them in a neoadjuvant fashion before doing surgery to try to decrease the risk of the tumour coming back. So in the future I think that these oncolytic immunotherapies will be very important and all of these four aspects to really be part of the armamentarium that we have for treating patients with melanoma.  Also expending this to other therapies as well: we know that experiments on carcinoma of the head and neck, we know that small cell lung cancer, bladder cancer, prostate, breast cancer and others also seem to have responses to these oncolytic immunotherapies so I think that we are just seeing the beginning of the use of them both in melanoma as well as in many other cancers.