Using All Modalities Key to Expanding Immunotherapy Success in Oncology

Patrick Hwu, MD

While immunotherapy is currently only beneficial in select cancers, it is possible for this type of treatment to eventually work for all patients, said Patrick Hwu, MD.

“There are potential targets for T cells on almost all cancers,” said Hwu, department chair, Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. “What we need to do is get the T cells activated in the body to recognize those targets, and we will get immunotherapy working in everybody.”

While checkpoint inhibitors may receive the most attention in the immunotherapy space, there are several other ways to manipulate the immune system to fight cancer, including T cell therapy and vaccines. Combinations, including those that pair different types of immunotherapies with each other as well as with targeted therapies, offer the most potential for long-term, durable responses with immunotherapies, said Hwu.

OncLive: What do you see as the biggest challenge in immunotherapy?

In an interview with OncLive, Hwu discussed the benefits of rational immunotherapy combinations, why some cancers respond better than others to immunotherapy, and why vaccines should not be discounted as effective immunotherapy options.Hwu: I think immunotherapy is eventually going to be useful in all cancers, but right now it’s only working in a subset of cancers, and within those cancers only a certain percentage of patients are responding. The big question is, “How do we get everybody to respond?”

What we do know is that the targets that the T cell recognizes are embedded in a certain molecule, called class 1, on the tumor. They are little peptides that are 9 amino acids approximately, and those targets exist on almost all cancer cells that we’ve looked at.

Do you see potential for combinations with targeted agents and immunotherapies?

There are potential targets for T cells on almost all cancers, but how do we get those T cells activated? One way is by adding these checkpoint antibodies; that works in activating the T cells that are already there. The other way is vaccines, and that proliferates the T cells in the body that are already there, and makes more of them to then recognize these antigens. The third way is T-cell therapy, which is when you grow large amounts of T cells outside of the body and give them back. All of these methods work the same way, and that is by a T cell coming in contact with a tumor, and killing that tumor cell. They are all important, and for different cancers, we are going to need different combinations of these approaches.What I am most excited about is adding immunotherapy to targeted therapy in a rational way. I think this is going to be very important. But we can’t just put any combination with anything. There are over 300 combinations with PD-1 agents right now, and many of them don’t have a lot of data behind them, so we are subjecting patients to trials without a lot of data, and that is not right.

We need to have much better science behind what to combine together. If we can get the right rational combinations for the right patients, we are going to go a long way toward getting long, durable responses for patients. That is why we are so excited about immunotherapy, because our immune cells can live in the body for a very long time. That is what our patients want; they want their cancer to be controlled not an extra month, but for the long-term.

Is there research looking at combining different types of immunotherapies?

What are the current theories regarding why certain cancers respond well to immunotherapies while others do not?

At ESMO, we presented a study that we did with a number of other investigators in collaboration with Genentech on an anti¬—PD-L1 antibody, plus a BRAF inhibitor, plus a MEK inhibitor. So we had 2 targeted agents and an immune agent for melanoma patients. The data looked really good.We are doing a study right now with anti¬—PD-1 with TIL cell therapy at MD Anderson. That was based on preclinical work with mouse models that Dr. Pang in my lab published. We do know that anti¬–PD-1 plus T-cell therapy works better than either by itself in mouse models, and Dr. Rodabe Amaria is testing that right now in patients with melanoma.Some of the cancers that are very immunogenic have a high mutational load, like the one I study, melanoma. The sun beats down, UV rays cause a lot of mutations, and those mutations look like foreign antigens. That is potentially why melanoma is more immunogenic. Smoking does the same thing in lung cancer. But kidney cancer is immunogenic, and it doesn’t have a lot of mutations. So it is not the only factor. I think there are inhibitory factors in the immune microenvironment. Anti¬—CTLA-4 and anti–PD-1 are just two ways to release the brakes. There are a lot of other inhibitory molecules in the immune microenvironment that have to be hit, and it may be different molecules for different kinds of cancer. We need to flip around the inhibitory signals. I think the targeted agents can, in many cases, do that, so we need to look at the targeted agents to change that environment.

You don’t hear as much about vaccines as you do other immunotherapies. What is it about this area that excites you?

The other possibility is that maybe we don’t have enough T cells. Taking the brakes off T cell production won’t work if you don’t have enough T cells to begin with. That is where T cell therapy and vaccines [can be effective, as] both will increase the number of immune cells.A lot of people have given up on vaccines, but I think vaccines are probably the most scalable way to distribute immunotherapy, and the most scalable way to get many more patients eventually responding to immunotherapy that are not. We’d probably have to combine that with many other methodologies, like anti¬—PD-1 and anti–CTLA-4, but that being said, we really need to think more about vaccines and work really hard on them.

T cells are great, but they are a more challenging therapy to scale than vaccines. We have 500,000 Americans at least in our country alone that die of cancer every year, so we need something that, first of all, works, but secondly is scalable to be given to everyone. Vaccines can do it. We cannot give up on them. I think they haven’t worked in the past because we’ve just given A, when we really need to give A, B, C, and sometimes D. We are really learning what A, B, C, and D are in our mouse models, and that is really exciting. We are really trying to get all the resources together to get those trials going in people.