Analyzing the Present and Future of Immunotherapy for Melanoma

As demonstrated in the phase 2 CheckMate-069 study, there is long-term potential for immunotherapy in the treatment of melanoma, especially as the trial proved a 42 percent improvement in overall survival (OS) for patients being treated with Yervoy (ipilimumab) and Opdivo (nivolumab) when compared with those being treated with Yervoy alone.

While there have been many recent advances in the field of melanoma regarding immunotherapy, there is much more is to come, says Antoni Ribas, a 2015 Giant of Cancer Care in Melanoma.

In an interview with CURE, Ribas, a professor of Medicine, Surgery and Molecular and Medical Pharmacology at the University of California, discusses what these data mean and where the field of immunotherapy in melanoma is headed.

How far have we come regarding immunotherapy in melanoma?

The advances in immunotherapy that are being discussed at meetings are based in two areas. First, we were taking away the breaks to the immune system so we can get the endogenous immune response that was already trying to be unleashed and attack the cancer. Or, we were creating an immune system in patients who don't have an immune system that's targeting the cancer. These areas are now the standard of care in some cancers.

Where is the field going to go over the next few years?

With the variety of therapies available, are there sequencing challenges?

We've seen several checkpoints being developed, such as ones that are foreign to PD-1, alone and now in combinations. The science is growing very rapidly to unleash as much as we can from an endogenous immune response to fight cancer.The science tells us that we can do better, that we can modulate the immune system in different ways. Patients who benefit from single-agent PD-1 blockade should only get that. It's very active, and has low toxicities in some cancers. The majority of patients will not benefit from that, so we have to understand why that is the case and then be able to combine it in a way that we can provide new treatments. It may be two drugs; it may be three drugs. Or, it may be the sequential use of different drugs. All of these are being tested, both preclinically and in the clinic.Right now, we probably have more drugs and potential combinations than we can test. The science is going to bring us to the right place, and only the clinical data will tell us what is too much, where we've gone too far, if toxicities are too much, or when we haven't done enough to where the immune system hasn't been turned on.

We are also going to personalize treatment more. We are going to try to figure out what's missing in every patient, and how we can turn it on. I think we're in a steep curve where we're learning a lot and we're going to improve in this field of therapies in the near future.

How do you go about managing the different side effects?

The mechanism of action for immunotherapies for cancer is turning on the immune system to the cancer. Obviously, whenever there are side effects, it's likely that's the immune system is attacking normal organs. That is something that needs to be recognized and treated appropriately.

These are different toxicities from chemotherapy drugs. The effects from these drugs need to be managed in different ways. In many cases, we'll have to tone down the immune system once we have tried to turn it on because we have gone too far.

When it comes to patients who don't respond, what questions do we need to answer?

We are starting to understand why some patients don't respond upfront. There are certain cancer phenotypes that are not sensitive to the immune system. What we're seeing now are certain transcriptions where those tumors are less sensitive to the immune system.

We're also seeing that mutational load is important. The higher the mutations, the more likely the immune system will recognize the cancer as something bad, as opposed to thinking that it is something normal that grows from inside. We have to incorporate this information and be able to select the right treatments for the right patients.

Anecdotally,what characteristics should a patient with melanoma have to consider immunuotherapy agents?

We're getting there and, I think in the near future, we'll make progress in this.Right now, besides PD-L1, we have limited ability to select patients. If you look at the science behind this, we know that, in the future, we'll be able to select patients for single-agent or combination therapy.

It will likely be a combination of the presence of immune cells in the tumor, of T cells, that are triggering PD-L1 expression and what those T cells are. Are they recognizing tumor antigens, and is the tumor something the immune system can recognize because it has high mutational loads and has a certain genetic profile that is permissive to an immune system? Those are questions we need to answer.

If we put all of this together, we think "should we just take out one checkpoint, probably PD-1, or should we do two, three or four checkpoints?" That's how it is going to allow us to select patients.

What ongoing clinical trials are you excited to see the results of?

There are a series of clinical trials that are combining PD-1 checkpoint inhibitors with other agents. Some of the clinical trials are trying to attack T cells in the tumors, and we have already seen success by combining Opdivo and Yervoy, which is already approved in the United States for melanoma. Otherwise, we're trying to inject things into tumors so the immune system will come and, at the same time, we're going to unleash it once it's there.

We're combining PD-1 blockade therapies with immune-activating antibodies, like CD137 or CD40, both of which are validated targets that turn on the immune system specifically. Once it gets into the tumor, it can be turned off, but now we block PD-1 so we do two things with the immune system simultaneously.

We can combine these agents with standard of care therapy and additional therapies. Also, with targeted therapies, there are certain combinations that will not cripple the function of the immune system cells, but will actually make the tumor more sensitive to the immune system.

I think we are in a great time to be applying this science to more patients.