A Perfect Pair: Expert Discusses the Future of Immunotherapy Combinations

Treatment for melanoma, lung, head and neck cancer, and others has greatly been changed by immunotherapy, which improves survival and provides long, durable responses for many patients.

The success of immunotherapies in those cancers — which are likely seeing a better rate of response due to their high mutational burden — is now paving the way for what are known as “cold” tumors, those that don’t have a heavy mutational burden or significant T-cell infiltration, said James Allison, Ph.D.

“There is enough progress being made across the board that I think we can start thinking about some of the colder tumors responding if we just keep studying and making rational combination decisions,” said Allison, professor and chair of Immunology at MD Anderson Cancer Center. “As we understand this better, we can rationally put two things together that won’t just duplicate or cancel each other out, but will do different things that can at least be additive, if not synergistic.”

What are you most excited about right now in the immunotherapy space?

In an interview with CURE, Allison discussed exciting advancements in immunotherapy combinations, the potential synergistic effects of radiation with immunotherapies, and considerations that must be made when combining other agents with immunotherapy.Some people are afraid to use the word “cure,” preferring to say that we’ve turned it into a chronic disease instead, but I know patients who are 10 or 15 years out after a single round of treatment with immunotherapy that considered themselves cured. So I don’t think it is so much of a stretch. The realization that we can cure even a fraction of people is exciting. It shows that it can at least be done. The most exciting single thing right now is the fact that the two-year survival of patients with metastatic melanoma who have received both Yervoy (ipilimumab) and Opdivo (nivolumab) is 60 percent. If the Yervoy response is any indication, it’s going to be much longer than that. That provides the excitement that we can get it to work in other cancer types.

What progress is being made in understanding why some types of cancers respond to immunotherapies, while others do not?

We are also gaining insight on how to rationally combine agents. Mechanist studies are really showing us a lot with these different checkpoint blockers and different mechanisms of action. It is too early in the trials yet to know, but we are learning a lot from analyzing the tissues of patients who respond and don’t respond. More importantly, we are looking at tumor tissues from patients who are on therapy, instead of just getting a baseline and seeing who will respond. There are signals for those who are on treatment, which can really tell you if you are going in the right direction or not.

There is a relationship that everybody talks about between mutational load and response rates. It’s an association, but generally, the kinds of cancers that have higher mutations because of carcinogen exposure — like melanoma and sunlight, and lung or bladder cancer and tobacco smoking —respond very well. But some of the colder tumors, the ones that don’t have a lot of mutations, that don’t have a lot of infiltration, like kidney cancer, have good responses still.

What type of agents do you see the most potential for in combination with immunotherapies?

There are tumors like prostate cancer, that are very poorly infiltrated and also have a low mutational load, that tend to respond less to monotherapy, but combinations haven’t been tried. We have a lot of data from an immunotherapy platform here at MD Anderson, and I think we know the right combinations to get it to respond.Most of the activity now, at least that I know about, is in radiation. The data that are coming out in lung cancer with immunotherapy and radiation combinations are remarkable. There is also some chemotherapy combination research going on.

Relatively few targeted therapies are being investigated with immunotherapies, although that research is happening. One of the problems is that there are so many options for combinations; the temptation is there to just combine something from column A, something from column B, and something from column C, and see if it works. That is the way it used to be done back in the empirical days of chemotherapy, but we know enough now to not do that.

Why might radiation be a good pair with immunotherapy?

With targeted therapies, we need to really be careful to put things together that make sense. If a targeted therapy inhibits the MAP-kinase pathway, for example, you may have a problem, because T cells use the MAP-kinase pathway to proliferate. If you shut that down, when you are starting an immune response, it may not be very good. On the other hand, if you got a good immune response, you might be able to use a targeted agent like that to prime it better when the immune system is not completely dependent on proliferation. Or, you can just dose it in a way where the drug is gone from the system by then, depending on what its half-life is. I don’t think enough attention has been given to scheduling like that.The radiation has to be done properly, in a way that does not wipe out the immune response. When you use radiation to kill cells, it releases antigens and causes inflammation so the dendritic cells, which are ultimately the ones that prime the T cells, rush in and start priming. If you are not doing something like that, you have to rely on the hope that something has happened already to prime the T cells. By actually killing a bunch of tumors with radiation, you cause that death and that wave of antigen release and inflammation to happen when you want it to, when the best time to give the drug is.

Oncologists are starting to modify how they do it, because if you do it and the immune cells come and then you blast them again, you are going to kill them. A number of oncologists are changing the way they look at radiation, and they are doing it in a way where they are not trying to kill every last cell, which used to be the goal, but instead only kill a fraction of them—enough to get a substantial antigen release that you can prime the response and let the immune system clean up.