Making CAR T cell therapy more effective for B-cell lymphoma treatment
Clayton Boldt, Ph.D.
Chimeric antigen receptor (CAR) T cells were approved by the FDA to treat relapsed and refractory large B-cell lymphoma in adults in 2017. There are now two FDA-approved CAR T cell therapies, and while these have significantly improved survival for many B-cell lymphoma patients, they are not effective for everyone.
While CAR T cell therapy has been effective for many, what challenges remain with this therapy?
CAR T cells offer a treatment option for patients who really did not have any hope before. It’s the first ever FDA-approved product for relapsed or refractory large B cell lymphoma, the most common type of non-Hodgkin lymphoma in the U.S. and the world. That’s a huge improvement for these patients.
On the other hand, while 80% of patients actually respond to CAR T cell therapy, only about 40% stay in remission long-term. So, there is room to improve its effectiveness.
There are also safety challenges with CAR T cell therapy. Currently, patients need anywhere from one to two weeks of hospitalization for this treatment. While that’s better than what’s required for certain chemotherapy treatments or stem cell transplants, we still have room to further optimize this product and cut down on the hospitalization period. We’re also seeing about a 1% risk of mortality from complications related to adverse events from CAR T cells, so we would certainly like to improve there.
Another challenge is the cost of treatment. The FDA-approved products are custom-made for each patient, so they require a cumbersome and expensive manufacturing process. On top of that is the added cost of hospitalization. Eventually, we would like to see this move to an outpatient setting with an off-the-shelf product, which could improve the safety and decrease costs.
Finally, because these products are patient-specific, it requires at least three to four weeks to manufacture the product. Sometimes patients with very aggressive lymphoma cannot wait that long. We’re currently seeing about 10-15% of patients referred for this therapy being unable to be treated because of this wait. Related to that is the fact that this therapy currently is only available at transplant centers because of the infrastructure that’s required, so there’s definitely room to improve accessibility as well.
You’re part of the team leading this flagship to address several of these challenges. How are you working to improve efficacy?
We’re studying the mechanisms of resistance to understand why some patients relapse or don’t respond at all to CAR T cell therapy. Broadly speaking, we’ve found two potential mechanisms, antigen escape and impaired T cell fitness.
Currently, these therapies only target CD19, so tumors are able to mutate and relapse with CD19 loss. We’re trying to understand why some tumors lose CD19. For these tumors, we’re working to develop CARs against new targets that are also expressed in the tumor cells. The long-term goal then would be to use a combination of CARs to target multiple molecules and minimize chances of immune escape.
On the other hand, about half of patients still have CD19 and relapse because of impaired T cell fitness. T cell fitness seems to be affected by multiple mechanisms, including chemotherapies they’ve been treated with or the tumor itself impairing T cell function. We’re trying to understand these various means of impairing T cell fitness, and the question for us is how to reverse and restore fitness to create a better quality CAR T product.
How about improving the safety profile of these cells?
We’ve collected blood and tumor samples from patients treated with CAR T cells at MD Anderson to try and understand why some patients experience much more severe toxicities. With CAR T cells, patients can experience cytokine release syndrome as well as neurological toxicities. While we understand what causes cytokine release syndrome, we don’t fully understand the causes of neurological toxicity. So that’s been an area of focus for us. We have found some potential mechanisms that cause neurological toxicity and would like to develop strategies to prevent it altogether. In fact, we anticipate launching a couple of clinical trials to address this in the near future.
You mentioned an off-the-shelf product in the future. How would that lower costs and improve accessibility?
We’re very excited to be working on developing an off-the-shelf product. I really think this is likely to be the future for cell therapies because the autologous approach is unlikely to work in every patient and the cost of patient-specific manufacturing isn’t sustainable.
The idea is to take T cells from a health donor and make CAR T cells that would be good for thousands of patients. There are very good gene editing technologies available now to make this type of therapy work. If we are able to develop off-the-shelf CAR T cells, we could use them across multiple cancer types by just altering the molecule they target.
This would not only decrease the time and costs of manufacturing, but you’re more likely to have T cells with better fitness because you’re using cells from a healthy donor. These products could also be more widely available at many more centers, even community hospitals, because the required infrastructure would be much less complex.
One major challenge to this approach is that donor T cells can be rejected by the host immune system. To prevent that, we’re evaluating gene editing technologies to prolong the persistence of T cells in these patients to achieve durable remissions.
The support of the Moon Shots Program allowed us to develop the infrastructure to be able to collect, save and analyze patient samples. We’ve collected blood and tumor samples from more than 100 patients treated with CAR T cells at serial time points. That’s something that is feasible entirely because of the Moon Shots funding. We’re doing extensive profiling, both immunologic and genomic, to try and understand the mechanisms of resistance and toxicity better in order to develop safer and more effective approaches.
The Moon Shot also allowed us to take on more high-risk/high-reward projects like the off-the-shelf program. It would have been difficult to initiate this through traditional funding mechanisms, because of a need to have preliminary data. But here, because of the Moon Shots Program, we could really get this program off the ground.