CAR-T Treatment for DIPG
CAR (chimeric antigen receptor) T cell treatment is a type of targeted immunotherapy that has had dramatic success in pediatric leukemia. More recently it has been applied in clinical trials for solid tumors of the central nervous system. The general concept of CAR T cell treatment is that immune cells are removed from the patient’s bloodstream and then modified to attack a particular protein of the cancer before being delivered back into the patient. In some cases, this can be done outpatient with limited side effects.
Overall CAR T cell engineering can take a little less than a month and the promise is that there will be little to no effect on other non-cancerous cells, thus limiting ancillary damage. Several different CAR T therapy options are being explored such as memory T cells that may provide a prolonged resistance to further cancer developments.
There are differing treatment strategies for CAR T, each focused on different delivery or target paths. Although still experimental in nature, the hope is that these will become mainline strategies in the effort to cure DIPG/DMG, medulloblastoma and other types of tumors.
We’re pleased to be able to be joined by Dr. Nick Vitanza from Seattle Children's Hospital to talk to us a little bit about CART and what makes it different and explain a little bit how it actually works. So I'll turn it over to you.
Dr. Nick Vitanza:
Thank you very much for this opportunity to talk about CAR-T cells with you all. I know there's a few misconceptions about it, but there's also lot of excitement. My hope is to just go through some basic things, not necessarily in particular about Seattle's program, but just in general, to help with the understanding of what this process is. I think, as we all know for a lot of pediatric brain tumors, most of the malignant tumors, when they come back or some diseases like DIPG in the beginning, radiation can only do so much and chemotherapy can only do so much. So these days, there's a very broad basket of things called immunotherapy, which are using the immune system to target the tumor. That's a wide variety of things you can use and only one thing in that bucket is CAR-T cells. CAR-T cells are really an engineering delivery method of a therapy.
CAR-T cells are going to vary a lot based on what you're targeting, how you engineer them, and the way different institutions run these trials in a lot of granular ways, like how often you dose or where you actually deliver the T-cells. There’s a lot of variability, and there should not be a reason to believe any one T-cell would act the same as another one on a different trial. There's fortunately going to be a lot of variability in this. One thing that you do with CAR T-cells, and I'll show just a few pictures here, is that essentially, you're taking out somebody's white blood cells, specifically their T-cells, which are the yellow cell there and you take them away from a patient, not an amount they'd miss, and then you engineer them so they have a new receptor on their surface. That receptor should be able to target things that are on the surface of the tumor.
So, they specifically will target the tumor and no other parts of the body. CAR T-cells really, when they're working in their best possible sense, are a targeted immunotherapy specific for a tumor. The proof of principle that this works was initially leukemia trials where targeting a molecule CD19 on leukemia led to fantastic results in children with leukemia. For example, children with current leukemia that got CAR T-cells had a 93% remission rate in the Seattle Children's study and about 60% of those patients ended up being long term survivors, which unfortunately, we know is not the norm for phase one trials. Based on that result, a lot of groups, what I'm showing here is specifically City of Hope, a mostly adult but also pediatric center in California, showed that they could give CAR T-cells directly into the brain of adults with brain tumors and spinal cord tumors. What you see here on the right is that they were able to get remissions of disease where the disease was going away and shrinking, both seen here on MRI and PET scan.
This work by Christine Brown at City of Hope and Mike Jensen was really the foundation that CNS CAR T-cells targeting brain tumors was possible. What we wanted to do in Seattle was map this out and find out what are the best things to target and we opened two trials that target two things, HER2 and EGFR. There are two separate trials called Brainchild-01 and Brainchild-02, and we enroll children. We remove their white blood cells. We engineer the CAR T-cells, which takes about 24 days and then children come back to Seattle and get their CAR T-cells delivered directly into the brain through a small little plastic button under the scalp and they either get the CAR T-cells directly into the tumor cavity, which is that localized area, arm A, or for children who unfortunately have disease in more than one area, they get the fluid put into the ventricles, which is a fluid system in the brain, which should allow the CAR T-cells to move around to multiple areas.
The way that we dose, and this will vary between studies, is with weekly dosing for most of our studies and most of our arms. Children come back and, as an outpatient totally in the clinic, will come to clinic and get these infusions on a weekly basis with a fourth week off and then a second course on a weekly basis where they often go up a dose level, so children are allowed to get more than one dose while they're on the trial. Then depending on how children do after the first two months, they can continue. Here, it says through course three through six, but we recently got approval from the FDA to treat indefinitely for children who are doing well.
Our dosing is a little different. It's not per weight, like with a lot of drugs. It's just a flat number of cells starting off at 10 million. And eventually, we're working up in our trials to a hundred million cells per dose, which we already are in some trials. Now, our first two trials didn't include DIPG, just as we were getting used to how CAR T-cells operate. But we developed a third trial, Brainchild-03, which targets a molecule B7-H3, which we're very excited about because we think it's something that's not on brain, but is on a large variety of pediatric brain tumors, including DIPG. For that trial, we opened a specific arm for children with DIPG RMC and the only difference in the treatment is that instead of every week, children get treatment every other week on that arm.
Across all these CAR T-cell studies, what we're doing is we're really engineering your own white blood cells, and then delivering them back into the brain with the hope that they will get to the tumor, engage with the tumor and CAR T-cells can really act as serial killers of tumors, where they can attack one cell, destroy it, move on to the next cell, destroy it. We're still learning what the limitations and potential benefits are of CAR T-cells, but there'll be a wide variety in studies, both on potential side effects, which could be based on what you're targeting, or how the CAR T-cells engineered or where you're delivering it. And so there could also be a lot of different benefits across different trials.
There’re several excellent centers that all have trials, and I would expect that we'll see variability in all of those things. It's going to take a few years until we learn what are the best targets, what are the best delivery systems. CAR T-cells for brain and spinal cord tumors are really in their infancy and it's going to take several years until we perfect this, start targeting more than one target at a time, find out the best place to deliver them. Those are all things that we, as a community, are working on together and I hope that we'll get there soon.
Are there different ages that are applicable for these types of treatments? Or is it something that's just a young adult oriented trial?
Dr. Nick Vitanza:
That's a great question. The FDA asked, when we opened our trials, we were the first pediatric center delivering them directly into the brain, that we start off enrolling children over 15 and our maximum age is 26. About the first year we had the trials open in 2018, we were treating 15 to 26. But after the first three patients on each trial, we were allowed to expand to all ages. For our trials, we treat 1 to 26 years of age across our trials. Different institutions are going to have different rules. Maybe not everyone is comfortable treating up to 26 depending on their pediatric institution. Maybe not everyone is comfortable treating down to the age of 1, depending on their delivery system.
Because we don't sedate children and because we don't have mandatory admissions, we've had younger children. Like we're treating a two-year-old now, who comes to clinic and watches his iPad and we numb the area over his infusion site, deliver the T-cells, then he's watched for a few hours and he is able to go home. So we've found it feasible so far for younger children, but each hospital will have different age requirements maybe based on what they expect out of their CAR T-cell and what their pediatric team is comfortable managing.
Fantastic. If people want to learn more, obviously there is going to be a link back to Dr. Vitanza's lab and more information about CAR T as well. Thank you for joining us.
Dr. Nick Vitanza:
Thank you all very much. If I could say just one more thing, there's a couple other excellent institutions who are also doing this work. Baylor, Stanford, City of Hope, Children's Hospital of Philadelphia. There’re other teams who have programs and there will be some variability and it's really just the augmentation of the T-cells and delivery which is the same. Hopefully as a community, all of these kinds of institutions working on this are going to make a lot of progress together.
And then chances are, there'll probably be more permutations of this as well. And sounds like a successful strategy. Thank you very much.