Stanford Medicine Newsletter Updates For the Local Community

 

The promise and pitfalls of cancer immunotherapy

Crystal Mackall, MD, is the lead investigator at Stanford for the new Parker Institute for Cancer Immunotherapy, a large-scale venture to use the immune system to treat cancer.

   

The concept of corralling the body’s immune system to combat cancer has been around for decades but recently has emerged as one of the most promising avenues of treatment.

Earlier this year, Silicon Valley entrepreneur and philanthropist Sean Parker launched the new Parker Institute for Cancer Immunotherapy, investing $250 million in a multi-institution effort that includes Stanford Medicine. The lead investigator at Stanford is Crystal Mackall, MD, a pediatric oncologist and associate director of the Stanford Cancer Institute, who discussed the venture.

Q: You have said that cancer immunotherapy was at one time considered “fringe science.” But now it’s one of the hottest areas in cancer treatment. What has changed?

Mackall: Very simply, we have seen results in the clinic. We have seen proof that it works, and that changes everything. You can do as many animal studies as you want, but if you can show that a patient with a disease that is incurable is cured or has great results, everybody sits up and takes notice. That’s what happened, starting around 2010. That was the inflection point, because that is when the clinical results started to be really such that you couldn’t ignore them.

Q: You have had some great success using immunotherapy to treat cancer in children. Tell us about that experience.

Mackall: I started working on this in the mid-1990s and frankly tried a lot of things that didn’t work so well. Maybe there was some benefit but not something that was black and white. But when we tested the use of genetically engineered T cells for leukemia, the results were just astounding. We were seeing patients whose leukemia was resistant to all previous therapies be put into remission to the point where you couldn’t find any leukemia within a month of first treatment and with just one dose. This was above and beyond anything I’d ever seen — or anything I’d ever imagined.

It wasn’t just us — and this is one of the most important points. Many groups started seeing this effect, and while the treatments varied a little across different hospitals, they all had the same dramatic results. When you start to see the same results across institutions, you know this is real.

Mackall uses engineered T cells to improve cancer outcomes, applying the body's immune system to attack cancer cells.

Q: And yet these therapies don’t work for every type of cancer and they don’t work for all patients. Do we know why that is?

Mackall: Those are the big questions the field is facing right now. Those are two of the three biggest questions: Why don’t they work in all patients? Why don’t they work in other diseases as well? And even when they work, is the tumor going to develop resistance? Because even if you put a patient in remission, you haven’t necessarily cured them. Now we are seeing there are ways, perhaps months down the road, in which the tumor reemerges. Those are the three biggest questions, and they certainly serve as a focus for my work going forward.

Q: Are those the primary pitfalls you see now in treatment?

Mackall: Yes. Immunotherapy comes in two different types. The work I’m leading here at Stanford and that I had been engaged in at the National Cancer Institute is using engineered T cells. In leukemia, that therapy works for 70 to 90 percent of kids who receive it. That’s a very high number. The other type of immunotherapy is called checkpoint inhibitors. These are antibodies that inhibit an inhibitor. It basically blocks a negative signal, so you get a positive. Those response rates are not as high. For most cancers, they are less than 50 percent. So that’s the big question: What is the difference between patients who respond and those who don’t respond? There is a lot of really intense work going on in this area.

Probably the area that I feel most passionately about — that I’m really trying to push the envelope on — is how can we make this incredibly dramatic result in childhood leukemia apply to other diseases. There are some diseases, even in childhood cancer, where we haven’t made progress in 50 years. It is unbelievable when you have a patient diagnosed with those diseases to have to sit with the family and tell them the survival rate is less than 20 percent and we’re not doing any better than we did in the 1970s. You hate to say it.

So from my point of view, that’s the big kahuna. Can we take the results in leukemia and achieve the same results in really difficult-to-treat cancers — like brain tumors, solid cancers of childhood, metastatic sarcomas? The answer is complicated. There isn’t just one thing that makes leukemia easier to treat than solid tumors. But that’s what we are working on, chipping away at it.

Q: How is the Parker Institute going to enhance your efforts and the efforts of others around the country?

Mackall: I think the most obvious answer is resources. There is a lot of money being put to the issue of cancer immunotherapy by Sean Parker. That in and of itself will drive progress. Most of the progress in this field right now is in the clinic. For immunotherapy, we are learning so much from clinical trials, but the challenge is that clinical trials are extremely expensive. Even when National Institutes of Health funding was at its peak, it was never a good mechanism for funding clinical trials. And now NIH funding is even less robust. The fact that the Parker Institute is putting big money into cancer therapy and is really interested in funding clinical trials — that is really important.

They also are making a very, very serious attempt at driving collaboration. That’s not to say there hasn’t been collaboration, but they are taking it to the next level. They are trying to create a virtual institute that spans universities and brings together leaders in the field. It’s an ambitious goal. So the collaborative approach is very important.

I think there’s also an awareness when you have something of this size and scope. It raises awareness and leads to all kinds of good things. It makes people think, “I’d like to invest in that.” It makes patients think, “I would like to avail myself of those clinical trials.” So I think raising awareness is really helpful.

Q: Are there clinical trials here that patients can take advantage of?

Mackall: The immunotherapy program here at Stanford Medicine has been in existence for a long time, well before the Parker Institute or I arrived. For the last 40 years or so, Stanford has been a leader in cancer immunotherapy, even when it was considered fringe. Stanford was one of the pioneers. Those cancer immunotherapy trials have continued to evolve and are ongoing. The lymphoma program pioneered by Ron Levy, MD, [professor of medicine] continues. The bone marrow transplant program, which is a form of cancer immunotherapy, has been one of the premier programs in the world for some time.

But we now are seeing cancer immunotherapy trials open for solid tumors. We now have checkpoint inhibitor trials and have opened several trials of adoptive cell therapy—the T cell engineering therapy. We have trials in ovarian cancer, lung cancer and ones soon to open in sarcoma. We anticipate there will be more — this is just a beginning.

 

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