Understanding Immunotherapy in Cancer: A Q&A with Antoni Ribas, MD, PhD

Antoni Ribas, MD, PhD

Targeted Oncologyspoke with Antoni Ribas, MD, PhD, director of the Tumor Immunology Program Area at UCLA's Jonsson Comprehensive Cancer Center, about the emerging role for immunotherapy in cancer.

What immunotherapies are approved to treat cancer?

Dr. Ribas:The first immunotherapies approved were cytokines that act to stimulate the immune system; these include interleukin-2 and interferons. These have fairly low activity and need to be given at high doses, which results in high toxicity for patients. Then came the concept of turning on the immune system by releasing its natural brakes. Although tumors may have stimulated an immune response, that immune response was eventually stopped because of these natural brakes.

Ipilimumab was the first immune checkpoint inhibitor developed, and resulted in a paradigm shift in how to turn on the immune system to fight cancer. Ipilimumab was approved for metastatic melanoma in 2011 by the FDA. The tumor activity of ipilimumab is arguably low—it is not a highly active agent. But, in patients where it works, it works very well. Those patients can have a response of more than a decade.

What are the potentially important immunotherapies now in clinical trials for cancer?

The most important ones now are the anti-PD-1 and anti-PD-L1 antibodies. These also release a brake on the immune system, but in this case, it’s different than the brake targeted by ipilimumab. The brake for these newer agents is in the effector phase of the immune response, when the killer cells are ready to attack the tumor but the tumor protects itself from the immune system through PD-L1, which is expressed on the tumor. Blocking PD-1 or PD-L1 results in exposure of the tumor to the immune system. These agents have shown an unprecedented response to an immunotherapy in cancer.

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The immunotherapies are approved for melanoma and kidney cancer. Are these newer PD-1 pathway antibodies being tested in a broader range of cancers?

There has always been something about melanoma that makes it more immunogenic, and it is still not clear exact what that is. Renal cell carcinomas and some lymphomas also have shown durable responses to certain immunotherapies. For response to interleukin and interferon, a tumor needs to have inherently more immunogenicity. As we started using immunotherapies with higher activity, such as PD-1 and PD-L1 antibodies, we saw that they had high activity in these generally immunogenic tumors. But now we see some activity in tumor types that were previously thought to be less or not at all responsive to immunotherapy, such as lung cancer.

What other agents or combination immunotherapies are being tested?

I am very excited about the PD-1 and PD-L1 agents being developed as part of combination therapy, particularly with ipilimumab or other immune checkpoint inhibitors. The other relevant immunotherapy is T-VEC, which is an oncolytic virus. This agent did show positive data in a randomized phase III melanoma trial. T-VEC does have some antitumor activity and can induce an immune response. I would assume that as a single agent; however, its use would be restricted to a very small patient population. But, for example, if it could turn some cancers from PD-1 or PD-L1—therapy nonresponsive to responsive, I think it would have a very high interest.

Can you describe this oncolytic immunotherapy approach?

T-VEC is a re-engineered oncolytic virus, a herpes simplex virus. It is a virus that is injected intratumorly, so it infects cells and produces progeny that cause the cell to lyse, killing the cell it infects. It has been designed to elicit an immune response because it also expresses GM-CSF, a white blood cell growth factor. So it induces an inflammatory change and attracts immune system cells because it expresses GM-CSF. It does not go from one cancer cell to another well. Because our immune systems have protection against the herpes virus, this re-engineered virus does not become an actual herpes virus infection; rather it induces a limited infection that exposes tumor antigens to the immune system. It’s a therapy that has low antitumor activity by itself and low ability to turn on the immune system. So you have to be restrictive about whom to give it to so that the patients that do receive it could see a potential benefit.

Are there other tumor types where an oncolytic virus such as T-VEC could be efficacious?

I think head and neck cancer would be another tumor type—any tumor where it would be relatively easy to inject the tumor itself. Some breast cancers also have multiple skin metastases, although this is not common, but that may be another application.

For the currently approved immunotherapies as well as the anti-PD-1 and PD-L1 antibodies that are still in trials, how do you decide which patients are candidates for these therapies?

I try to give the PD-1 and PD-L1 antibodies to as many patients with melanoma as I can, which is what I treat. If I were treating other cancer types, I would also want to give these therapies to as many patients as possible. We will learn with time which patients are likely to respond or not. These therapies directly impact the interaction of the immune system and the cancer cell, as opposed to ipilimumab, which acts where the immune system is being turned on, which is farther away from the actual tumor. So, it is harder to develop biomarkers of response to ipilimumab.

There are few drawbacks to the PD-1 and PD-L1 agents that I see. The toxicity is relatively low and the potential benefit is very high. However, in a patient for whom a little bit of toxicity will lead to major problems because of comorbid conditions, ipilimumab would not be appropriate. The reality is that the majority of patients who receive ipilimumab do not have side effects, but they also don’t have benefit.

How do you see immunotherapy as a cancer treatment evolving in the next 5 to 10 years?

I think there is a really high potential for immunotherapies to have a great impact and to be a major approach in cancer therapy. A challenge is understanding how the PD-1 and PD-L1 agents work and potentially turning the patients who currently don’t respond into responders. If this can be achieved, these agents would likely be among the first treatments to be considered by clinicians as therapies for many cancers.

What do community oncologists need to be aware of when considering immunotherapy or recommending an immunotherapy clinical trial for patients?