Imaging Immune Therapies in Brain Tumor Patients



by Kayt Sukel

February 05, 2018

Q&A with Samuel Cheshier, M.D., Ph.D. 

Cheshier-Samuel-80Director of Pediatric Surgical Neuro-Oncology  
Primary Children's Hospital
Huntsman Cancer Institute  
 
Dana Foundation Grantee: 2014-16 

Brain tumors are the most common type of cancer occurring in children aged 14 and younger—as well as the leading cause of cancer death in that age group, according to the American Brain Tumor Association. Doctors find determining a patient’s prognosis, especially a child’s prognosis, after diagnosing a brain tumor a difficult task at best. Current treatments, including radiation and chemotherapies, also can result in so-called late effects, unintended consequences that can harm development and cognition. Immunotherapies, treatments that harness the body’s natural immune system to help fight malignant brain tumors, may provide a safer alternative for pediatric and adult patients alike. Samuel Cheshier, M.D., Ph.D., a pediatric neurosurgeon now at the University of Utah, is working on new technologies to improve immunotherapy treatments and track their effectiveness over time.

What first drew your interest to pediatric neurosurgery?

I grew up very impoverished. And I knew becoming a doctor was a good way to get out of that kind of environment. My first roommate at UCLA—we’re still friends today—wanted to be a neurosurgeon because his father was a neurosurgeon. I was a good student and he was very cool. So we struck a bargain—he’d help me become cool, and I’d help him become a better student to reach his goal. In honoring that bargain, I realized just how great neurosurgery was.

During my residency at Stanford, they created a pediatric neurosurgeon rotation. I did that for six months and I really liked it. I liked the patients, I liked interacting with the families, and I liked the work. To be honest, as crazy as it sounds, it’s actually a very happy type of neurosurgery in comparison to adult neurosurgery. With adult brain cancer, about 80% is incurable. In pediatric brain cancers, however, it’s the opposite—even if the tumors are malignant, about 80% have a potential for a cure. That’s remarkably hopeful.

The prognoses for brain tumors remains stubbornly poor in both children and adults. Why is that?

In terms of pediatrics, the prognosis is poor if you have a particular pathology that is incurable. And that is a significant number of tumors, like glioblastoma, high grade glioma, diffuse intrinsic pontine glioma and midline glioma. If you get any malignant brain cancer as a kid, less than three years old, you can’t get radiation treatment. And without radiation, there’s absolutely zero chance of a cure.

That said, gliomas in both adults and children are just notoriously hard to treat. You can surgically resect every bit of it you can see in the imaging and know that your patient is still going to die—they may have a few extra months of life but they will not survive that tumor. These tumors are also often located in areas that you can’t resect, like the brain stem. Which means you can’t get rid of the tumor surgically at all.

Finally, so many treatments we have available currently just aren’t very effective at getting rid of brain tumors. For many years, there has been little progress made in extending the lives of patients who have brain tumors. I’d like to see that change.

What might help bring about that change?

I believe immunotherapy is going to make a huge difference in cancer care for all types of cancer including brain cancer. In the next ten years, I think we will back away from the harsh chemotherapy and radiation protocols as our first line of treatment. Instead, we’ll use combinations of immunotherapy modifications or immunological signatures to treat these stubborn tumors. But to do so, we need imaging techniques that will allow us to assess accurately the amount of important immune cells, like macrophages, that are present in the tumor.

We know that having lots of macrophages in a tumor, in and of itself, has some prognostic value. Generally speaking, the more macrophages you have, the worse off you are. But this may also indicate that you are a good candidate for a macrophage stimulating immunotherapy, which signals these cells to directly attack cancer cells and basically eat away the tumor.

Tell me more about this potential macrophage stimulating immunotherapy.

The immune system possesses the molecular machinery to distinguish between self and non-self. But cancer can trick this system, whether it’s caused by mutations or some type of aberrant expression of protein, to hide from the immune system. But if we can find a way for the immune system to recognize cancer as foreign and attack it, we can set things up for these macrophages to muster an immune response that will actually get rid of it.

In my research, we use a macrophage checkpoint inhibitor, anti-CD47. This way, the immune system macrophages purposely recognize the tumor and attack it yet leave normal cells alone. And using this kind of intervention, we expect fewer side effects than radiation or chemotherapy.

I don’t think that we will completely move away from radiation and chemotherapy as treatments. But we can use super low levels of these, levels low enough that have no therapeutic effects by themselves, but to make cancer cells more immunogenic [capable of inducing an immune response], boosting the immunotherapy and thereby more successfully treating the tumors.

Why might immunotherapies be more beneficial to pediatric patients?

These kids have their whole lives ahead of them. If we can avoid high doses of chemotherapy and radiation, we are avoiding lifelong side effects and debilitation caused by those very treatments. We are also avoiding potential secondary cancers that can be caused by the treatments, too.

You used Ferumoxytol, a nanoparticular-based imaging agent, as part of your work. How does imaging play into development of immunotherapies?

Feromoxytol is actually an FDA-approved iron supplement. It’s something that’s been used in patients who have received a bone marrow transplant—and it works without hurting your kidneys. For years, it’s been used off-label as an imaging agent for cardiac studies, too. So it’s been very easy to apply to other applications like brain tumor imaging since it is already available. It’s not very expensive and it’s easy to use.

But more importantly, this compound really lights up in the MRI machine as a contrast agent. After a few days, this agent is eaten by the macrophages and resides inside the tissue of those immune cells. It then becomes a signal of macrophage contact in the tumor. We have confirmed, through our pilot study, that Ferumoxytol resides within the macrophages of malignant brain tumors, directly correlating with the macrophage signal in these tumors.

This is important because when we start giving macrophage-promoting immunotherapies, there will be inflammation occurring in the tumor. With old imaging techniques, we wouldn’t know whether that inflammation is tumor growth or an immune reaction. An immune reaction itself can cause symptoms, which offers a big diagnostic dilemma. Is the tumor growing through this treatment and we need to switch to something else? Or is this just inflammation? This imaging technique can allow us to know that any inflammation is due to more macrophages coming in without requiring radiation or a biopsy. And with that information, we know that (a) our immune therapy is working as it should and (b) the swelling is due to the immune reaction and we can carry on through that.

Furthermore, we may also be able to use this for T-cell immunotherapy, as T-cells, when they kill off the cancer cells, stimulate macrophages to come in and clean up the debris. So it’s possible we could use macrophages as a biomarker for these other types of immunotherapies as well.

How do you plan to follow your pilot study?

We’ve finished the pilot study in adults and are now funding up a similar pilot study in children. Once that is done and verified, we could propose to study hundreds, if not thousands, of patients to determine if the macrophage load, as indicated by Ferumoxytol, is indicative of the prognostic value that we expect. But the most exciting avenue, and what I plan to do next, is to use this in clinical trials of the macrophage promoting immunotherapies that are currently coming online. We can do a trial alongside that to see whether the macrophages are moving into the tumor and the degree of macrophage infiltration in response to the immunotherapy.

You’ve said that Ferumoxytol can also help with vascular malformations in the brain. How?

Our work has shown that Ferumoxytol imaging of vascular malformations can be just as accurate as a formal cerebral angiogram—and that can help us better determine whether a malformation is present or not. This is huge for pediatric neurosurgery because the normal angiogram involves a lot of radiation. We may actually not need the angiogram anymore.

The other thing that is exciting is that we can use Ferumoxytol imaging to help us better understand which blood vessels in the brain are feeding the tumors and vascular malformations and which are draining these abnormal structures. In neurosurgery, you want to take the vessels feeding the tumor or vascular malformation out first and those draining the tumor or vascular malformation last. If you can take out the input first, it’s essentially a bloodless, and as such, a safer surgery. Right now, we can only get this information via a formal angiogram. So if we can use Ferumoxytol and more advanced imaging protocols, we can make surgery safer and improve overall care of our patients while we expose them to less ionizing radiation.

Your work comes from the close marriage of basic science and applied surgery. Why is this combination so important to novel and innovative surgical interventions?

It comes down to the combination of anatomical knowledge, access to the operating room, access to the necessary patient samples, and then working together to find ways to solve problems.

There is already a lot of great, cool stuff out there with potential for treatments in other areas. Without working together, it would be impossible to know about what’s all available. But if we can work together, and use these already available compounds in different ways, it has the potential to impact different branches of science and medicine in quite unexpected ways. And very positive impacts, too. So it pays to work together, to look at these different compounds that already exist and are FDA-approved, and just go discover what they can do. 

 Cheshier-Lab-Feb2018-400
 Samuel Cheshier in his lab. Photo courtesy of Dr. Cheshier.

 

Further Reading (scientific publications resulting from this work;):

Anti-CD47 Treatment Stimulates Phagocytosis of Glioblastomaby M1 and M2 Polarized Macrophages and Promotes M1 Polarized Macrophages InVivo

Wide-Field Dynamic Monitoring of Immune Cell Trafficking in Murine Models of Glioblastoma