From 300 patients to 1,600, City of Hope remains at the forefront of cell therapy
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When Healio | Cell Therapy Next visited City of Hope in 2019, the institute boasted a robust cell therapy program, having treated 300 patients with the then-newly approved therapy.
Today, City of Hope reports more than 1,600 patients have received cell therapy treatment, and the institution has completed or is conducting more than 80 clinical trials across many cancer types, including 35 in solid tumors. City of Hope is also a leader in the development of novel CAR T-cell platforms and has 16 active trials evaluating internally developed CAR T-cell therapies.
Healio had the chance to sit down with Christine E. Brown, PhD, deputy director of City of Hope’s T Cell Therapeutics Research Laboratories, and discuss the changes over the past 5 years.
Healio: What is the biggest achievement you’ve seen in the cell therapy arena since we met 5 years ago?
Brown: In 2019, chimeric antigen receptor T-cell therapy was just recently approved by the FDA for a subset of blood cancers — B cell-derived leukemia and lymphomas. Even multiple myeloma hadn’t been approved.
I started working with Stephen J. Forman, MD, and other colleagues in 2001 and wanted to build a program focused around CAR T-cell therapy and its potential to transform care for patients with incurable cancers.
There were a lot of naysayers back then, especially in my area of malignant brain tumors. Immunotherapy was still at its infancy.
When you visited in 2019 it was an exciting time, because we could see the potential and, in a subset of cancers, patients were experiencing remarkable outcomes. It really gave you the chills.
You saw the impact for these patients who had no other therapeutic options. But we knew back then it wasn’t all cancers — solid tumors were more of a challenge — and it wasn’t all patients.
The most exciting thing in the last 5 years is we have moved from focusing on T cells engineered with a single-targeted CAR to more advanced approaches of using these living drugs as delivery vehicles, engineering them to target multiple antigens, and changing how they interact with the microenvironment. Therefore, the types of therapies being brought to clinic are more complex.
To me, that means we’re on the cusp of seeing some remarkable advances in solid tumors and other cancers, even some of the blood cancers such as acute myeloid leukemia, and others that have not yet been FDA approved.
We are also seeing that this therapy can have remarkable impact for patients outside of cancer in autoimmunity.
City of Hope has a program where we have been one of the first to engineer T regulatory cells with a CAR-T for graft-versus-host disease. And we’re hoping to apply these learnings to other T cell-based autoimmune diseases.
Healio: What have been the biggest hurdles in the past 5 years? How has City of Hope worked past them?
Brown: Delivery of CAR T-cells, especially in solid tumors, is really important. How do we get cells to where we need them to go?
These are living drugs. They can traffic throughout the body, but cancers often put up these walls that make it difficult for these immune cells to penetrate. If we can break down those barriers through local delivery, that could have advantages.
In City of Hope’s brain tumor program, we’ve been leading this local delivery approach. Other groups were putting these cells into the blood as they would for systemic cancers. The trial we published in Nature Medicine looked at putting the cells into the resected tumor cavity and also into the cerebrospinal fluid through the lateral ventricle.
Our experience suggests that this approach is patient friendly. The device used for local delivery is under the scalp and seems to be well tolerated by patients. We are seeing this more widely accepted in the field and being readily adopted by other institutions.
At City of Hope, we are also looking at whether local regional delivery into the CSF requires lymphodepletion like is done for systemic CAR T-cell therapy. What is the best dosing regimen? How many times should we give these cells? What should be the cell dose?
There are still important lessons to be learned and we’re working at City of Hope with our partners at other institutions to learn how best to implement that. But the local regional delivery seems to be an important aspect when we’re trying to treat malignant brain tumors.
Additionally, we are attempting local delivery in other solid tumors. We have a trial in ovarian cancer where we are also delivering these cells locally into the peritoneum, and there’s been ideas with liver cancer and other cancers.
Are there advantages for other solid tumors to local regionally deliver? That is still being worked out but there’s opportunity to initiate a response by getting a bolus of the therapy to where it needs to go.
I’m passionate about finding a way to improve outcomes for patients with glioblastoma and other incurable brain tumors. The field’s advances are at the cusp of realizing transformative changes in patient outcomes as we apply lessons learn about these therapies in early phase trials — the advanced engineering, the understanding of how these cells work, how they interact with the microenvironment, and rationally designing more complex circuitry and ways of addressing the challenges of solid tumors, tumor heterogeneity and trafficking.
Where the therapy is now, what’s been approved and what will be approved in 5 years is going be very different.
Q: What is the next goal in your sights?
Brown: Optimizing CAR T cell therapy for brain tumors has been my passion. I am fortunate to have an incredible team at City of Hope, especially Behnam Badie, MD, who leads our clinical studies. And we just published the largest phase 1 clinical trial reporting on 58 response-evaluable patients. This trial included the most comprehensive clinical experience in patients with glioblastoma and other high-grade gliomas treated with CAR-T, and we showed that in a subset of patients there was meaningful clinical benefit.
We had two complete responses; we had some partial responses; and we had some patients who remained disease-free longer than they did from their initial standard of care. In the recurrent setting, you would expect disease to come back more quickly. But after CAR-T, the disease was controlled for longer than their initial therapy.
That’s incredibly exciting, because there is a possibility for success with this therapy in one of the most difficult-to-treat cancers.
What keeps me up at night is why isn’t it having an impact in all patients we treat? Why are some patients resistant? Why do some patients recur right through therapy? We have this opportunity to learn from our clinical trial and really understand the cancer, and how it responds to this therapy — and how to make the therapy more potent against the array of mechanisms that the cancer uses to evade the immune system and CAR-T. We’re really excited.
In the next year, we hope to open two new clinical trials, targeting a combination of antigens and making these T cells resistant to certain molecules produced in the microenvironment of glioblastoma that suppress immune responses.
It gets to the more advanced engineering. Most likely, we’re not going to go into these solid tumors targeting a single antigen without other modifications. We’re going to engineer these cells in ways that modifies the microenvironment, that targets multiple antigens to deal with tumor heterogeneity, and possibly other modifications to improve T cell fitness.
At City of Hope, we have a lot of trials ongoing and about to be initiated in many different disease settings, testing a lot of different hypotheses. We are always getting at the question of how do we improve response rates and durability in a wide range of cancers. In glioblastoma, specifically because of the learnings from the patients that we’ve treated, we’ve made the decision to pursue some very doable changes.
We’re targeting two antigens that are very attractive to address heterogeneity, engineering these cells to resist TGF-beta, an important suppressive cytokine in the tumor microenvironment. I hope that will be sufficient for the majority of patients, but we’ll learn if we need three antigens because there are many ways to evade the immune system.
We hope in early 2025 to start these trials, really implementing the learnings from our patients before to get to that transformative response. Then, hopefully, a phase 2.
We, as a field, are building better therapies. The question is in that reverse translation approach: how is the cancer responding? We can only learn the limitations of the therapy by doing these early phase trials.
Some hurdles we know — trafficking, heterogeneity, etc. — but then how will that tumor respond? Will it find a new path to evade the immune system? There will be more challenges that we haven’t even identified.
Then there’s safety. How do you build more powerful therapies while maintaining safety? You’re pushing this therapy to really be more potent — to recognize more cancer cells. But we’re treating tumors in the brain, a very sensitive organ. And we want to leave these individuals with a high quality of life.
These are all questions we can’t answer until we test these new ideas and new engineering approaches in patients. We can get hints of that in our preclinical models, but it really takes those careful dose-seeking clinical studies.
We saw this with CD19 CAR T-cell therapy. We had to learn to manage cytokine release syndrome, neurotoxicity and other safety concerns at the same time as we learned how to manufacture these cells and build CARs to give the best therapeutic response.
Those of us that understand the dire need of these patients with glioblastoma and other incurable brain tumors are collaborating and discussing ways that we can get an approved cellular therapy in this disease. City of Hope is doing really important work leading the efforts in this charge.
Q: Is there still collaboration between the leading cell therapy institutions?
Brown: Absolutely. If you look at this year, there were several landmark studies published in malignant brain tumors. Ours was the most complete, finished phase 1 trial published, but other groups at Massachusetts General Hospital, University of Pennsylvania and Stanford University published their first cohort of patients treated with their CAR T-cell platform. All of them are learning from what City of Hope has led, and locally delivering these cells to the cerebrospinal fluid.
It really seems that it’s an approach that is working well in this disease setting to get around the blood-brain barrier.
You saw this with CD19 CAR T-cell therapy; this is the important aspect about how we learn from each institution, and each trial builds on past experience while also testing unique ideas. And so we’ve been happy to help our colleagues.
Q: In our previous piece, we discussed City of Hope’s “long-term plan to cure cancer.” Where are you in that long-term plan?
Brown: Cure is a word that you use cautiously. When I started in this field, I didn’t think we would use that word for individuals treated with refractory B-cell malignancies with CD19 CAR T-cell therapy.
There are patients who are more than 10 years out from their initial treatments. So that word cure is being used and so it seems that this therapy can be curative in some patients.
We have an individual we treated at City of Hope who was on his third recurrence with a high-grade brain tumor recurring as quickly as 3 months, and he is now 5 years out. I don’t know when we’ll use that term cure, but it definitely is remarkable.
I hope I will be using that term next time we speak. Science is a path and we’re on the right path.
I remain incredibly optimistic. In the next 5 years, we’re going to see remarkable breakthroughs for cell therapy, for solid tumors, autoimmunity and other difficult-to-treat diseases that will benefit from CAR-Ts as treatment options. There’s a lot of excitement ahead.
- Reference:
- Brown CE, et al. Nat Med. 2024;doi:10.1038/s41591-024-02875-1.
- For more information:
- Christine E. Brown, PhD, can be reached at cbrown@coh.org.
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