Combined melanoma treatments improves survival

18 December 2018

Interview with

Howard Kaufman, Massachusetts General Hospital

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Melanoma, or skin cancer, is the fifth most common cancer, and rising. Medical therapies have not kept pace, and in some countries melanoma is one of the top ten killers of people. Now, Howard Kaufman and his team from Massachusetts General Hospital have begun to develop a therapy that uses the patient's own immune system to attack the cancer. Chris Smith heard how...

Howard - The immune system protects our body from foreign invaders such as bacteria and viruses but it can also recognise damaged or injured cells. And so, when a cell becomes a cancer cell the immune system can tag it, and in some cases it can destroy it.

Chris - The problem is that cancers carry inbuilt mechanisms to deflect the immune system, so that they can grow unhindered. And so, to be successful a therapy needs to somehow surmount this natural immune defence and persuade the immune system to regard the cancer as hostile. To make this happen the Massachusetts team have developed a modified virus that can selectively grow in cancer cells. As well as destroying the tumor where it's injected, the growth of the virus also provokes the immune system to attack the cancer, and subsequently to then patrol the rest of the body ferreting out tumour that has spread elsewhere.

Howard - So these viruses are what we call attenuated, meaning they're a little bit weaker so they don't cause as many side effects as a normal virus would cause. This particular virus is a herpes virus which normally would cause a cold sore. And the genes that cause some of the pathology are removed, and it has the added benefit that it seems to be able to replicate more efficiently in a cancer cell. And it's not able to replicate in a normal cell. And this is the basis by which oncolytic viruses are particularly well suited to treat cancer.

Chris - On their own though, the viruses only trigger a successful response in about a quarter of patients. But what happens if the viral therapy is combined with other treatments that attack melanoma in different ways. One class of drugs already approved to do this are agents called immune checkpoint inhibitors. These block the ability of cancer cells to deflect the immune system making it harder for tumour cells to hide.

Howard - So the way I like to describe it to my patients, is that if you get a viral infection you need your immune system to eradicate the virus but then you want to shut that immune system off, because when you get a cold or the flu, the reason you feel miserable is largely because the immune system is being overactive. So there are a set of molecules called checkpoints and these turn the immune system off. And cancer, being the sneaky disease that it is, has learned how to use these checkpoints to turn the immune system off. And this allows the cancer to grow. So checkpoint inhibitors are a new set of drugs that block this kind of shut off switch. And when you shut that down the immune system stays active for a longer period of time and this allows then, the immune system to deal with the cancer.

Chris - And the combination of the checkpoint inhibitor drug with the modified virus can greatly boost response rates.

Howard - We combined the virus with checkpoint inhibitors, which are also approved to treat melanoma, and the early results of those clinical trials are showing tremendous promise, where we're seeing almost a doubling, if not more, of the response rate without an increase in side effects.

Chris - Which is great news. But it does still mean that a significant number of individuals nevertheless fail to make an effective immune response against their cancer. The same results are seen in experimental mice with melanoma. Part of the problem seems to be that the therapy itself triggers the cancer to increase its own production of other immune bypassing signals, including one called PD-L1. The good news is that drugs exist to block that too. And when these are added to the mix, at least in mice, the results are very impressive.

Howard - When we put the three drugs together, which hasn't been done before in humans, we actually saw almost 100 percent response in the animals. And this suggests that the three drug regimen might be a particularly effective way to treat patients. And all three of these drugs are already FDA approved as single agents. And another important point that we saw in the studies, was that because this was so effective we were able to lower the dose of almost all of the agents. And so it suggests that we might not have to use as high of a dose and that means we may not have to deal with as many side effects.

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