Immunotherapy At ASCO: The Cancer Research Institute On What To Watch

Jill O’Donnell-Tormey is the chief executive officer and director of scientific affairs of the Cancer Research Institute, a New York-based nonprofit that awards research grants and fellowships to scientists working in the area of cancer immunotherapy. O’Donnell-Tormey is excited by the progress that’s been made of late in many different technologies aimed at harnessing the immune system to fight cancer. Among them: engineered viruses, checkpoint inhibitors (drugs that block immune-suppressing proteins) and chimeric antigen receptor T-cells (CARTs), which are personalized therapies that involve removing T-cells from the blood of patients and engineering them to attack their particular cancers.

I asked O’Donnell-Tormey to take a look at the abstracts submitted for this year’s annual meeting of the American Society of Clinical Oncology (ASCO), which begins today in Chicago, and to provide guidance on what to watch in the field of immunotherapy. Here are edited excerpts from our conversation.

Weintraub: Checkpoint inhibitors such as Merck’s Keytruda (pembrolizumab) and Bristol-Myers Squibb ’s ‎Opdivo (nivolumab) have already greatly improved the prognosis for patients with melanoma and lung cancer. What are some of the other cancers where checkpoint inhibitors are also being investigated that you think look promising?

O’Donnell-Tormey: We’re starting to see decent responses in kidney and bladder cancer, relapsed Hodgkin’s lymphoma, and recurrent and metastatic head and neck cancers. The original trials for [Opdivo] and [Keytruda] were reported last year. Now you’re seeing three-year survival and two-year survival, and in renal cell carcinoma with [Opdivo] we’re seeing five-year survival from a phase 1 study and three years from a phase 2. Most of these are positive.

Weintraub: There’s seems to be a growing sentiment that immunotherapy treatments will work better in combinations. So which combinations are most interesting to look at during the ASCO conference?

O’Donnell-Tormey: We’re starting to see combination trials of the checkpoint inhibitors with new targets like 4-1BB. Pfizer and Merck have a study there. It’s early, but looking like it’s safe. And they’re getting overall response rates in the high 20% range. This is something to watch going forward. There’s also an OX40 agonist plus the anti-PD-L1 from Genentech. That’s in advanced solid tumors.

There are multiple things happening in the tumor micro-environment and in the cancer itself, so we need to come in with a multi-pronged attack. That’s what’s exciting about these combinations—we’re starting to come in from different angles and different mechanisms. That’s where the future is, but it’s a little bit early to say one combination is going to be better than the other. It may come down to figuring out which combinations work in certain subsets of patients.

Since 2014 there’s been a six-and-a-half-fold increase in the number of combination trials with immunotherapies. The majority of those are going to read out in the next two or three years.

Weintraub: What do you think are some of the most important things that have been learned in the past year about the importance of looking for those subsets of people who may respond much better than the overall population?

O’Donnell-Tormey: Look at colon cancer as an example. Colon cancer was never considered to be responsive to immunotherapy. But there is a subset of colorectal cancers that are called “microsatellite instable.” A trial showed that [Keytruda] had a major response in those patients. But the microsatellite stable patients did not respond.

I think that’s where the future is going. Immunotherapy has a role, but it’s going to be personalized immunotherapy. That being said, there are challenges. For example, the biomarker that has gotten the most press is PD-L1 expression. But that seems to be a big quagmire, really, because there are differing results. First of all, when you look at Merck or BMS or Genentech , they will report that in some cases, responses were not always associated with PD-L1 expression. And then on top of that, they all use different criteria for measuring PD-L1 expression.

Weintraub: I know there have been some questions about the side effect profiles of some of these immunotherapies. What will people be looking at during ASCO about that, especially when you start looking at these drugs in combination?

O’Donnell-Tormey: That’s always the first thing that comes to everybody’s lips when you talk about combinations—the adverse events. In these combinations, they seem to be basically safe. Whatever side effects are happening seem to be manageable.

Weintraub: What’s your opinion of some of the other types of immunotherapies, like the CAR-T cells and the engineered viruses? Where do they fit in, and do you think they’ll also be looked at in combination?

O’Donnell-Tormey: I do think the oncolytic viruses are very interesting, because you’re getting more bang for your buck. They are preferentially killing the cancer cells, and you also have the viral component, which in and of itself attracts immune recognition and response. So I think that’s an exciting technology. But even with the Amgen virus [Imlygic], which is the only one that’s approved right now, the responses are modest. It’s in combination that you push the positive side of things. Amgen and Merck are collaborating on a trial there.

With the CAR-T cells, the excitement will be when it moves to solid tumors. That’s going to be about picking the right target. CD19 is a perfect target for the B-cell hematological malignancies. I don’t know what the right target is for solid tumors. But in talking to the people that work in that area, they seem to be very optimistic they’ll be able to target solid tumors.

Overall the future for all of these immunotherapy approaches is bright. We’re continuing to see immunotherapies expand to larger patient populations and different cancer types. I think this is potentially going to be a way to treat all cancers.