Dr Vitanza Discusses HER2-Specific CAR-T Therapy for Young Patients With R/R Brain, Spinal Cord Tumors

Nicholas Vitanza, MD, Seattle Children’s, Washington, shares the initial results from the phase 1 BrainChild-01 immunotherapy clinical trial, which suggests that CAR-T therapy may be a feasible treatment option for young patients with relapsed/refractory (R/R) brain and central nervous system (CNS) tumors.

Transcript

Hi. My name is Nick Vitanza. I'm a pediatric neuro-oncologist at Seattle Children's, where I am also the DIPG research lead and the CNS CAR T-cell lead. At the Ben Towne Center for Childhood Cancer Research at Seattle Children's Research Institute, I run an independent lab focused on looking for cures for aggressive pediatric brain and spinal cord tumors.

The reason that we started running these CNS CAR T-cell trials for pediatric brain and spinal cord tumors is we know there's a subset of these tumors that can be cured with conventional chemotherapy and radiation, but it doesn't cure all tumors, and even for the ones that it does, they are quite toxic treatments that have lots of long-term impairments for those children.

There is also specifically some tumors like diffuse intrinsic pontine glioma (DIPG) and diffuse midline gliomas where there's no cure at all with any conventional means. We've been eager to try to find novel therapies. For pediatric leukemia, using CAR T-cell therapy has been incredibly effective here through trials that have been run for over a decade.

We were really determined to try to transition some of the lessons learned from those trials and our own specific understanding from our large neuro-oncology program, led under the directorship of Sarah Leary, to build trials that were using CAR T-cell specific for children with pediatric brain and spinal cord tumors.

Our publication is essentially the preliminary information we learned from the first 3 patients which we did on clinical trial. The clinical trial was called BrainChild-01. What we're doing is using HER2-specific CAR T-cells for HER2-positive brain and spinal cord tumors that have either relapsed or been refractory to prior therapy.

We've made a couple augmentations to standard CAR T-cell approaches for other diseases. For solid tumors and leukemia, CAR T-cells are given directly into the blood, because that's the best compartment to get to the disease, or literally where the disease is in the case of leukemia.

For our trials, we used an intracranial delivery system. We call that local regional delivery of CAR T-cells. This was pioneered by Christine Brown and Mike Jensen at the City of Hope, where they have continued to run really successful, innovative trials.

We used a similar paradigm where we generate CAR T-cells in a bulk product, separate it into individual doses that we can freeze down for patients, and then outpatient in our clinic on a weekly basis, we can thaw those individual doses and deliver the HER2-specific CAR T-cells directly into the brain exactly at the location where the tumor is. That's been informed by the adult experience, but also by the preclinical experience where we've seen the mouse models that local regional delivery is superior to a systemic delivery, at least from what we can tell so far.

We designed this study and we began enrolling patients. The first 3 patients that we treated, we were able to generate the CAR T-cell products that we needed to deliver the therapy. We didn't see any dose-limiting toxicities in those patients. There weren't major toxicities that they were experiencing, although we did see some effects that they were having, like fevers and headaches.

It wasn't exactly surprising, but it was quite impressive how almost metronomic it was, where the headaches and the fevers were occurring with each dose, again not necessarily showing efficacy of the treatment, but that some on target inflammatory effect is happening. The other surprising thing is that we have so many CSF samples from our children when they are enrolled, because they have CNS catheters in place, most commonly something called an Ommaya. We deliver the CAR T-cells there, but we also can remove CSF, spinal fluid, from that.

We are able to run this kind of innovative, correlative studies on a regular basis that hasn't been done in pediatric studies before, because you normally don't have that much access to the compartment.

What we saw is that certain cytokines like CXCL10 and CCL2 were getting elevated with the treatment. These are interesting, because they are cytokines that previous people had shown are critical to immune cell trafficking in tumors, and in some cases even have immune cells are going to enter the tumor and then initiate the inflammatory cytotoxic effect.

The fact that we were seeing some of these correlations that were preclinically mapped out wasn't a complete surprise, but it was validating to see that we found some of these things happening.

Pediatric patients with brain and spinal cord tumors are a hugely in need population. We also need to think about this from an ethical perspective, but also even a little bit deeper from a quality of life perspective. We want to find curative treatments that are also feasible in a child's life schedule.

The fact that we are able to deliver CAR T-cells directly into the brain in an outpatient setting on a weekly basis, and that children are able to do that and spend a majority of the time outside of the hospital, at least in the preliminary phases, and we've seen this also across some other studies that we have opened that we are yet to publish on, that this is a feasible approach.

You can manufacture CAR T-cells. You can deliver them into the brain, and that children can receive this in the clinic and don't need prolonged, expansive monitoring.

The life of the CAR T-cells in the CNS compartment is just distinct from the systemic compartment. With current technologies, I don't think anyone is achieving long-term surveillance in the populations and the CNS. We still have a lot of learning to do about the microenvironment and how that's possible.

I think what we've done is help open the doors that you can have repeated local regional CAR T-cell trials for children. It all depends on your target, and your intervals, and a lot of other things that we are working as a community to figure out. This overall approach looks like it is likely possible.

Pediatric neuro-oncology isn't immune to some of the other systemic problems in our healthcare system, where there can be a discrepancy in the quality of care or what things are available, based on where you are diagnosed or where you are.

We do let international patients onto our trials, but no matter how hard we work, it continues to be a little bit cumbersome and clunky to get them here, be prepared for the trial, and be in a new environment. Even when we just extend that to other states and other regions, it can be difficult for patients to fly and receive their treatments.

Our dose-limiting toxicity period, or our observation period, is 2 months. That's, again, a big ask for children, even if it's outpatient, to be in a new city for 2 months during that observation period. Those are obstacles in that we need to have better support systems that are in place for all of pediatric cancer, where it's really not just the funding of the innovative trials, which we need more of, but also for the supportive care that these children go through, having an understanding of what a vast departure this is from a normal childhood life. They don't have the same mechanisms of support built in that, not all, but most adults with cancer would go through during their care. There's a lot of infrastructure that can still be built out and collaboration on those fronts.

We've developed a very robust pipeline. We've treated almost 400 children with CAR T-cells when you include leukemia, solid tumors, and brain tumors at Seattle Children's. This has been going on for a long time. It's a relatively well-oiled machine where children can have their case reviewed by us for no cost. We can get insurance clearance to do the appropriate staining of their tumor to make sure that the markers are present, and it makes sense for them to enroll. Then the enrollment procedure, we have dedicated social workers research staff. That includes nurse practitioners, clinical research leaders that are able to help the patients be comfortable here, collect the right samples on the right days, help them with housing, guide them through the entire process in a very holistic way.

At Seattle Children's, we do a neuro-oncology brain tumor board once a week. We review any internal patients or external patients that would like a review by our team. That doesn't include any cost. We have a long track record of participating with other hospitals and families remotely to give care advice or guidance and access to clinical trials, of which we have many, not just CNS CAR T-cells.

Specifically for the CAR T-cell programs, the BrainChild-01, 02, and 03 trials that are open now, and BrainChild-01 that's described in the Nature Medicine paper, we have a platform where we obtain insurance approval to get the staining done for the tissue to make sure that they have access to the trial. We review eligibility criteria and do remote visits with families before they come, to make sure that it's really the best option for them, and they have as good as possible an understanding as they could.

Then when they come out here, they come up to Seattle the first time for 3 days and they do their enrollment, their apheresis to collect their CAR T-cells, and then they are actually able to return home. During that month at home, they are able to do other treatments, but we stay in close touch to let them know how their CAR T-cells are growing. We make sure that they have access to the things they need when they return. That month gives us a runway to make sure we are as prepared as possible when the CAR T-cells are ready to go and ready to infuse.

From overall access, the CAR T-cells are paid for by the trial. There's no cost to enter the trial. We get insurance approval for anything that is not specifically clinical trial-related, anything that falls under normal observation interval. Anything that's trial-specific is paid for by the trial.

There's still financial burden, obviously the travel for the trial, but we try to ease that as much as possible and provide housing through Ronald McDonald or partnerships with local hotels. It's a cornerstone of our overall clinical trial program that we try to give children as much access as possible. Like for our trial in particular, we didn't say that you had to be newly diagnosed, that you had to have very specific parameters. You can have refractory disease. You can have recurrent disease. You can have metastatic disease. There are different arms that can cater to different patients. As few patients as possible we turn away because of the eligibility reasons, but also because of socioeconomic reasons that make travel hard.

We do have some tumors like medulloblastoma where we have what we would consider straightforward to deliver therapies, craniospinal radiation, several cycles of maintenance chemotherapy, and then cure rates of 70 to 75%.

Often, when we first meet children and set plans for their initial therapy, and there are a lot of curative diseases in pediatric neuro-oncology. For some diseases that come back, there's rarely another curative option. At that point, we immediately initiate what clinical trials which might already have been in the discussion for high-risk patients. When we start discussing what clinical trials might be an option and whether that's through some of our consortiums like the Pediatric Neuro-Oncology Consortium, PNOC, or DIPG-specific consortiums, what are the best fit for them where they are in their care.

For some of those children, it ends up being CAR T-cells, but for some patients, other things make most sense for them depending on the age of the kid, what their performance score is, what their overall goals are, what quality of life is like for them, how much travel is allowed.

It's really important, just like palliative care discussions, for children with DIPG, which is, unfortunately, a fatal disease, we have those children meet the palliative care team within their first month of being diagnosed. Even thought the median life expectancy is 11 months, we don't wait until things become really refractory, the treatment, we don't wait until progression to bring those services in.

We think of clinical trials the same way. We have a really robust program, and for high-risk kids, for kids that are early in their initial relapse treatment, we start thinking about what is the best clinical trial fit for them.

That's a really good collaborative relationships with other hospitals around the country. At any given time, the best option for you might be someplace else. While we try to have every trial option open here, we also find it very valuable to have big, open-door policies with other hospitals so that we review their cases, whether it's CHOC, or Texas Children's, or Boston. And they do the same for us, so that as a community, we can work out what is the best clinical trial option for children.