Immunotherapy researcher Gordon Freeman takes stock

It had been almost a year since I had last visited pioneering cancer researcher Gordon Freeman in his office at Dana-Farber. On this blustery fall day I was using a cane, hoping that the reason for my limp and sore thigh was tendon and tissue strain, not new cancer or complications from treatment, recent surgery, and radiation.

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Gordon Freeman

The security guard in the lobby printed me a temporary ID card and pointed the way to the staff elevator that would take me to the fifth floor.

“You’ll have to swipe the ID once you get in the elevator,” she said. “Otherwise you won’t be able to get up there.”

The elevator door opened. I stepped out and walked down the hallway to Freeman’s office. It was in this building that  Freeman had conceived of and conducted a seminal experiment that eventually led to current cancer immunotherapy treatments such as nivolumab and pembrolizumab. I had written about this research after my first meeting with Freeman (read the chapter here).

Since that time, the distinguished immunologist had been mentioned in media coverage as being on the short list for Nobel Prize. He hadn’t won, but he was hardly discouraged. He seemed to realize the fickleness and opacity of the process.

Indeed, Freeman seemed upbeat and cautiously optimistic about the continued success that immunotherapy was having in clinical trials, for various types of cancers.

An edited transcript of our conversation follows below. It touches upon a number of  topics, including Freeman’s thoughts on what’s next in immunotherapy, whether response rates will be improved, and whether the promise of immunotherapy, heralded in glowing advertisements and optimistic media coverage,  is reality or hyperbole.

Immunopatient:  Just thinking back since our initial conversation, and it’s been almost a year, nivolumab obviously has been approved for different cancers since then. Are you surprised that it seems to have performed so well against various forms of cancer in various clinical trials?

Freeman:  Am I surprised? No. We had a period when we thought of cancer as one disease and then we went to a period where we thought of cancer as 200 diseases. To the immune system, cancer is more like one disease.

The immune system is looking at what’s different about the cancerous cell. It’s looking at how many targets in the cancerous cell it can attack.

Immunopatient:  If the immune system even recognizes the cancer cell in the first place.

Freeman:  Yeah. There’s some tumors that have lots of changes, lots of mutations, like melanoma and lung cancer, which are good targets, as is something like head and neck cancer, which is often caused by papillomavirus, HPV. A virus is totally foreign to the immune system. That’s a good target for the immunotherapy, because it’s got a big difference.

Other tumors like those in prostate cancer are tougher because there are fewer changes in the tumors.

Immunopatient:  Where are we now with immunotherapy? I read someone recently say we’re about where the Ford Model T was in the history of cars. Do you think that’s an accurate analogy? Are we really that early in the game?

Freeman:  Yeah. Where we are now is monotherapy ‑‑ therapy with one of the immunotherapy agents. We’re at the dawn of combination therapy. Things like PD‑1 (nivolumab) plus CTLA‑4 (ipilimumab) is now an approved drug in melanoma, and is being tested in many other situations with success.

The problem with that combo is it’s more toxic and requires a lot more medical management, more adverse events. Where we are now is finding the right combination that is effective and safe. There was just a report that, right now, there are more than 800 clinical trials of the immunotherapy agents singly or together with other agents, with something like 160,000 slots available.

There’s just an amazing amount of effort going into finding what works and is safe.

Immunopatient: Do you think the so‑called Moonshot to fight cancer has galvanized people and helped move things forward?

Freeman:  These agents and trials have been going on for years, well before the Moonshot, but the Moonshot can organize it, publicize it, make the results available quicker, and make people more aware of what’s available.

We’ve really kicked the door open and taken a step through.

Immunotherapy is the real deal, and there are so many good ideas out there of combining things, that they need funding support and the Moonshot really can provide that support. That’s going to bring better success, faster.

Immunopatient: You seem optimistic and excited. But are there any challenges or things that you worry about in the broad area of immunotherapy, whether that be the business side, the research side, the funding side, or the cost side for patients?

Freeman:  It being overhyped is a concern because, right now, it’s about a 20 percent response rate. A response means your tumor shrinks more than 30 percent. It doesn’t mean your tumor disappears or you’re totally cured.

The percentage of people who have a tumor that shrinks 100 percent or 98 percent, it’s less than that 20 percent. It’s a subset of that. You don’t want to overhype this and have unrealistic expectations.

Immunopatient:  I recently saw a Time magazine from 1980 and interferon was on the cover as the being the new potential cure for cancer. The media has hyped these developments in the past.

Freeman:  I remember talking to a group of journalists. Then we had a quote on, I think they quoted us on NPR or so, but at the end, it was sort of, they said, “We’ve heard this before. There’s always big promises, and we’ll see.” This is the real deal but it’s not the real deal for every last person.

Immunopatient:  One of the big questions is how to get these immune therapies to work for a larger number of people. Where are we at in that? Is that work that is going on at your level at the lab, or is it more at the clinical level, or both?

Freeman:  It’s both. You really need the lab to provide the pipeline. To put a therapy in a clinical trial, you need logic and justification. That’s provided by scientists from the lab doing a model experiment, usually in a mouse, and finding that the agents work in a mouse.

Also, I think what’s coming now is some of the combinations are surprising. For instance, radiation and immunotherapy can work together. Five years ago if you’ve had asked me, “How does radiation work?” I would have said, “It just kills cells.”

It does that, but when you kill cells the body needs to vacuum them up and clean up. It turns out that when the immune cells clean up, they present these dead tumor cells to the immune system. That lets the immune system see them and get activated. So, something like radiation can also stimulate the immune system.

You also wouldn’t think that chemotherapy would work with immunotherapy. Chemotherapy refers to an incredibly broad range of treatments, but most of them are designed to kill a dividing cell.

Since the immune system is dividing cells, immunotherapy and chemotherapy don’t seem like a natural pairing. But people are looking now at some of the chemotherapies, and finding that some of them can work with the immune system to be even better. Some of the clinical trials are combining certain chemos with PD‑1 blockers.

Immunopatient: It’s still relatively early days to use the cure word for immunotherapy. You have durable long‑term responses, certainly. But that’s a big word to be throwing around.

Freeman:  After how many years do you call it a cure? What do you think needs to be done to establish that you’ve got a cure?

Immunopatient:  What do I think? I don’t know. It’s just such a big word. Is there an accepted medical definition?

Freeman:  No. Is it 5‑year survival, 10‑year, 20‑year? Turns to computer and pulls up a graph. This shows Steve Hodi and Jedd Wolchok, they’re the physicians who’ve done the clinical trials. This follows like 2,000 patients who were treated with CTLA‑4 (ipilimumab or Yervoy). This starts out in, I believe, the mid 1990s.

These patients, now some have been followed out as long as 10 years. What it shows for CTLA‑4 is that 70, 80 percent of the people don’t do well. But when you get out to this year 3, that if you’re OK at year 3, you’re likely to be OK at year 4, 5, 6, 7, 8, 9, 10.

These are the people who’ve received ipi, and you only receive ipi for a little while that first year. They haven’t had any ipi treatment for, out here, out for nine years and they’re still with us. Now, PD‑1 hasn’t been studied as long, about five years.

Turns to computer and pulls up another graph.  This is a study of like a hundred melanoma patients on PD‑1. The good thing is the PD‑1 does somewhat better than the CTLA‑4 or ipi, so there’s about 35 percent of people who are still doing well at like five years. Again, smaller numbers, not as many years out, but it looks good.

You’ve had over the years both IPI and PD‑1, right?

Immunopatient:  Yes. I’m a good example of the promise, but maybe the limitations of immunotherapies because I’ve responded very well in the lung and the lymph nodes. To some extent maybe you could say the brain now, too.

Because it’s been over a year, coming up on a year and a half since there’s been any tumor activity in the brain.

Freeman: In the brain you probably got radiation?

Immunopatient:  Yeah, focused radiation. The Cyberknife. Not whole brain radiation.

Freeman:  That might be an example of radiation therapy working with immunotherapy. Again, that’s an anecdote, and a speculation, but people are really doing the combination of and analyzing does radiation work with immunotherapy? What’s the right dose and staging way to give it?

Immunopatient: How has immunotherapy changed the way we think about cancer?

Freeman: It’s really turned cancer on its head because it used to be that the more mutations, the more ways that cancer would find to grow. Now it seems that the real key is to stop the cancer cell from turning off the immune system.

The thing about a lot of the old cancer drugs is they hit like one target. If you hit just one target, there’s so many little varieties in the cancer cell that they find a way around it. When you hit one target, what happens is it responds and you do well for a year.

Then it becomes resistant and stops working, because that one in a billion cancer cell’s found a way around it.

What’s good about the immune response is you’ve got millions of T‑cell receptors and millions of different B‑cell receptors, and hundreds of what are called pattern recognition molecules. You’ve got an evolving system that can change as the tumor changes.

That’s the critical realization. What that does, actually, is it makes some of the worst cancers like melanoma and lung cancer more treatable. They have a really high number of mutations, and so they have the most targets once you stop the cancer from turning off the immune system.

You’ve not got a one‑trick pony.

 

 

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