Catherine Bollard and her team have an ambitious goal:
To establish CAR T-cell therapies as the standard of care for pediatric solid tumors within the next 10 years. CAR Ts have made little to no clinical traction in solid tumors thus far, despite their success in some blood cancers.
Bollard, director of the Center for Cancer and Immunology Research at Children’s National in Washington, D.C., and her team, called NexTGen, received the 2022 Cancer Grand Challenges Award funded by Cancer Research UK, NCI, and the Mark Foundation for Cancer Research.
The award will fund the NexTGen project over the next five years. Bollard’s team, co-led by Martin Pule, senior lecturer and director of the Cancer Institute Chimeric Antigen Receptor Programme at University College London, was one of four teams to receive the award in 2022.
The other three teams are:
- eDyNAmiC, which seeks to gain new insights into extrachromosomal DNA, and translate them into new treatments for people with some of the challenging forms of cancer
- PROMINENT, which will investigate how cells and tissues maintain ‘normal’ phenotypes while harboring oncogenic mutations and how they transition to become a tumor.
- CANCAN, which will focus on cachexia, a debilitating wasting syndrome characterized by extensive weight loss from both skeletal muscle and fatty tissue.
The NexTGen project’s focus on pediatric cancers addresses an unmet need.
The survival curves of relapsed and refractory pediatric brain tumors and sarcomas are nearly identical from those of 30 years ago, Bollard said.
The team’s patient advocates, parents of pediatric cancer survivors, noted that if their children relapsed today, they would receive the same treatments as children did 10 or 20 years prior.
Bollard’s team is uniquely equipped to respond to this problem. According to Bollard, there were two things that made their project stand out among the stiff competition: a plan to immediately initiate a clinical trial, and the diversity of expertise on their team.
“What has set us apart from other Grand Challenges, is that we’re actually starting work on the clinical trial work package at the beginning, with three cutting-edge clinical trials,” Bollard said to The Cancer Letter. “Because we know that there are some questions that you can’t answer in a mouse or in the test tube. There are some answers that you can only get addressed in the clinic.”
The team’s initial clinical trials are going to evaluate three agents, including a B7-H3 (also known as CD276) CAR T product with engineered resistance to TGF-β, a potent immunosuppressive cytokine in the tumor microenvironment.
“Bringing together the TGF-β story was work actually I started over 20 years ago at Baylor College of Medicine, mainly in the liquid cancer setting. So, this opportunity to now study it better in the solid tumor setting is very exciting to me,” Bollard said.
The team tasked with developing and testing these next generation CAR T products is comprised of scientists and clinicians across eight institutions throughout the U.S., U.K. and France, with expertise in immunology, proteomics, and mathematics.
Bollard said patient advocates play an integral role in the project.
“We do have real partnership with our patient advocates and our Cancer Grand Challenge team. They are integral to every single work package. That, I think, also sets us apart. They all have very unique stories. Many are parents who have lost children to pediatric solid tumors, but we also have a survivor of one of the pediatric solid tumors that we’re trying to address. It’s really so key that we hear from them and understand more from the community what their needs are as well, as part of this,” Bollard said.
Bollard works with patient advocates to better inform parents about the importance of research and sample donation. These critical samples and tissues are necessary for discoveries to be made, Bollard said.
The clinical trials will not end with the B7-H3-targeted CAR Ts. Bollard described the project which is broken into six work packages: two discovery modules designed to: 1) Identify novel targets for CAR T-cell therapy for pediatric brain tumors and sarcomas and other pediatric solid tumors, and 2) Define the tumor microenvironment and the immune-evasion strategies of the TME specifically within pediatric solid tumors.
The discovery phase of the project would lead to the development of additional novel CAR T products, which could be tested in pre-clinical and clinical settings.
The final stage of the project will be focused on data harmonization to ensure that findings are shared with the broader community.
Bollard spoke with Jacquelyn Cobb, reporter with The Cancer Letter. A video recording of the conversation is available here.
Jacquelyn Cobb: Right off the bat, congratulations on the Cancer Grand Challenges Award. That must feel amazing.
Catherine Bollard: Thank you. Yes, very much so. It’s a real honor, and we were very privileged to receive this award, with very stiff competition in the field.
Absolutely. Can you tell me more about your winning NexTGen project? How did it evolve?
CB: It really evolved between me and my collaborator and partner here (at Children’s National), Dr. Russell Cruz, and reaching out to Drs. Straathof and Pule at University College of London. We have a common link through our times at Baylor College of Medicine, where we all grew up in the field of cell therapy.
Obviously, that was really fertile training ground for all of us. It’s just been so wonderful to come together again after all these years.
That’s what’s so awesome about the Cancer Grand Challenge. It brings together people who may never have worked together before—we’ve got a lot of people like that—people who haven’t worked together for a long time, and then people from very diverse backgrounds within the scientific realm.
That means that the team is really bringing in very new ideas from mathematical modeling, engineering, all the way to cell therapy, immunotherapy, and immunology. So, I think, this is what really excites and energizes us to be part of this great team, to address the Cancer Grand Challenge of how to better target pediatric solid tumors.
Can you tell me the goals and deliverables for this project, specifically?
CB: Our overall vision is that within 10 years, we want cell therapy, specifically CAR T-cell therapy, to be standard of care for pediatric solid tumors. So that’s a very ambitious vision.
So, within that, we have six work packages which have pretty defined goals. The first work package is to identify new targets specific to pediatric solid tumors that can be targeted by engineered T cells.
The second work package is to understand the tumor microenvironment in pediatric solid tumors—understanding there’s been a lot of work done in adult solid tumors, but a lot less in pediatric solid tumors.
Work package three is then to bring those two discovery work packages together to engineer the next generation T-cell products that will target these new antigens and will overcome the immunosuppressive tumor microenvironment.
And then work package four will take those products from work package three, these new engineered T-cell products, and will test them in novel preclinical models.
Typically, a lot of us just use murine models, but work package four is looking at other sorts of preclinical models, like ‘tumor on a chip’ and other models to help us understand how these cells function pre-clinically. Then, work package five is eventually to get these cells to the clinic.
What has set us apart from other grand challenges is that we’re actually starting work package five—the clinical trial work package—at the beginning, with three cutting edge clinical trials. Because we know that there are some questions that you can’t answer in a mouse or in the test tube. There are some answers that you can only get addressed in the clinic.
So, we have three novel cell therapies already that we want to test in these parallel clinical trials that are being run through the U.K. and the U.S. So, that’s really cutting-edge and innovative and we’ll learn from those trials.
The discovery work packages will learn from them, not just in terms of the samples that we’ll collect, but also in terms of the outcome data and the immunobiology, etc.
Then we have a sixth work package, which is our data harmonization work package, to bring us all together and make sure that we have data sharing and are able to really ensure that our ideas are not only shared within our bigger group, but then ultimately shared with the community at large.
We do have real partnership with our patient advocates and our Cancer Grand Challenge team. They are integral to every single work package. That, I think, also sets us apart. They all have very unique stories.
Many are parents who have lost children to pediatric solid tumors, but we also have a survivor of one of the pediatric solid tumors that we’re trying to address. It’s really so key that we hear from them and understand more from the community about what their needs are as well, as part of this program.
That is amazing. Huge in scope.
CB: Right. It’s a grand challenge!
Can you tell me what the $25 million award will do for your team? Which CAR T targets are you focusing on for brain cancers and sarcomas?
CB: Right now, the work package five clinical trials are going to evaluate a B7-H3 (also known as CD276) CAR T product that we are going to also engineer to render the T-cells resistant to TGF-β, which we know is a really potent immune suppressive cytokine in the tumor microenvironment.
So, that’s the product we’re taking to the clinic in pediatric sarcomas and pediatric brain tumors.
But we’re also going a step further at evaluating the T-cell platform that we engineer. In one of the protocols, the one that’s being developed at Children’s National, we will actually be engineering T-cells that are already trained to target PRAME, which is a cancer/testis antigen expressed quite widely in these pediatric solid tumors.
This will allow us to compare our approach with the standard approach, which is just expanding non-specific T-cells and engineering them. So, we’re going to expand T-cells that we already know are tumor killing and make them even better with gene engineering. And we’ll be running those studies in parallel with UCL in the same disease. I’m quite excited to see how the two approaches stack up against each other.
To follow up on that question, I haven’t seen any existing CAR Ts for brain cancers and sarcomas. In terms of five-year survival rates in children, it’s about 20% for glioblastoma and 20% to 30% for metastatic Ewing sarcoma. Is this a primary unmet need in pediatric cancer?
CB: Absolutely. If you look at the survival curves, even from 30 years ago, for children with relapsed/refractory sarcomas and brain tumors, they have not changed much. I mean, that’s how pitiful it is.
Some of our advocates yesterday—when we had one of our quarterly meetings—was telling the story about the fact that if their child relapsed today, they would get the exact same treatment that they did 10 or 20 years ago. That’s how sobering it is about the lack of progress.
One of the brain cancers we’re going after is DIPG (childhood diffuse intrinsic pontine glioma), and for those children, they only have a median overall survival of 10 months. So this is truly heartbreaking and really a major area of unmet need.
Absolutely. What are the unique challenges of targeting solid tumors with CAR Ts? What makes it more difficult compared to blood cancers?
CB: There are two main reasons. Firstly, I don’t think we’ve got the right targets yet. For blood cancers, CD19 seemed to be a home run for B cell malignancies, but if you look at CAR T for acute myeloid leukemia, they haven’t had the same home run.
And it’s partly because of the antigens you have to target. And similarly, with solid tumors, this is the same problem: we just don’t have great targets yet.
That’s part of our discovery in work package one—to really look beyond conventional antigens and look specifically at pediatric solid tumors for what antigens they are expressing. So that’s one big problem to solve.
Then the second problem is the tumor microenvironment, which is really armed in such a way that it’s not of great interest for the tumor to have T cells go in and attack it.
But, I think with blood cancers, it’s sort of more circulating and maybe it is easier for the T cells to get there, despite the tumor immune evasion strategies. Whereas when you are trying to get into the cores of solid tumors, which are armed with all these immunosuppressive molecules and cells, etc., that just makes it a big challenge.
That is why understanding that tumor microenvironment better, and how we can attack it in a way to make it more amenable to T-cell killing, is what’s so critical as part of our initiative.
Similarly, you mentioned in your talk at the British ambassador’s residence that pediatric cancers are biologically distinct from adult cancers. Can you speak more about this and why we can’t rely on the “trickle down” approach from research in adult cancers?
CB: If you look at the biology of pediatric cancers, firstly, they just don’t have the same mutation burden that adult cancers have.
So, to find the sorts of small molecules that have really been a big advancement in adult solid tumors is just very unlikely in pediatric solid cancers. That’s why we really need to look at another strategy like engineered T cells.
In addition, checkpoint inhibitors, outside of Hodgkin lymphoma in pediatrics, have really had little to no effect in the pediatric setting, especially in pediatric solid tumors.
I mean, it’s remarkable how little efficacy is shown there, and it’s because, again, the tumor microenvironment and what immune cells are present is very different and sparse.
So, we have to add more T cells to that environment. And checkpoint inhibitors, which have been a big advance in adult solid tumors, are not the way to address this problem.
Shifting back to you and your team, I’d love to hear more about how the interdisciplinary and multicenter nature of your team contributes to your research.
CB: I really want to emphasize the diversity, because it’s not just a bunch of cell therapists who’ve been collaborating for years coming together to do more of the same old, same old.
This is bringing together groups that have never worked together or haven’t worked together for a long time, coupled with bringing people in from different disciplines, which really makes for very interesting conversations and really great new ideas are going to come out of this. I can already see that.
So, that’s really the secret sauce that we have: the diversity within the group plus—and I can’t emphasize this enough—the integral engagement from our patient advocates.
Without that community voice and engagement, I don’t think we are going to get much traction. Because you have to understand, a lot of these discovery work packages are going to require parental consent for biopsies and, sadly, in some cases, autopsies. Those sorts of materials are going to be absolutely key.
So, one part of our work with the patient advocates is how to better inform parents about the importance of research and sample donation, etc., which is key to allowing these discoveries to be made.
Yes. It’s such a hard conversation to have.
CB: Right. Especially at a time when it’s the saddest time in their lives.
Absolutely. So, how has your past research brought you to this project?
CB: Bringing together the TGF-β story was work actually I started over 20 years ago at Baylor, mainly in the liquid cancer setting. This opportunity to now study it better in the solid tumor setting is very exciting to me.
Plus, the platform of being able to combine engineered T cells with the physiologic T cell platform, like the PRAME-specific T cells, using that in a combination strategy (with gene engineering)—that’s what we are bringing to the table: this ability to combine two platforms together in a very novel way.
To me, it’s coming from 20 plus years of developing in the field, at a time when the field was so young and new. To get to where we are now is really exciting to me.
It’s also very exciting to me, because we have younger scientists and trainees and physician scientists on our team, because a big part of our initiative is to train and grow the next generation of scientists and physician scientists in this space.
I also see that what I “bring to the table” is years of mentoring the next generation. That’s also really exciting, because being able to do it on an international level is terrific.
What are the next steps for you and your team? What’s coming next?
CB: I mean, the immediate next step is to start the clinical trials. We have an ambitious timeline to start in the next, hopefully, six months.
At the same time, currently what we are doing is a lot of work looking at different solid tumors and looking at the tumor microenvironment in those tumors, as well as starting with the antigen discovery work.
We also have some other engineered products that we want to test pre-clinically, because we’re always thinking of our end goal. Even though we’re about to start these upfront clinical trials, at the end of our five years, we want to deliver next generation products. So, we need to start now to evaluate what we have pre-clinically as well.
So, all of this is going on at the same time, and right now there’s so much activity. We have our first face to face meeting in January, so we’re all gearing up to get all that data together to present there, which will be the first opportunity for us all to get together in person, which will be really special, and a great opportunity for sharing ideas, etc.
And January will come just like that.
CB: I know; right?
That’s why there’s a lot of work to be done, and that’s why it is so important that we are working with our advocates to help us work with parents to be able to get the critical samples and tissues that we need to do these studies.
Well, thank you so much Dr. Bollard. Is there anything that we missed?
CB: No, hopefully I gave you more than enough information. We really do believe in our vision and we really want to deliver on it in the next 10 years. So, there’s no time to stop.
