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Developing a Pause Button for CAR T-Cell Therapy
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Chimeric antigen receptor T-cell therapy has proven to be a life-changing development for those with advanced, treatment refractory leukemia and lymphoma for whom other therapies have proven ineffective. But if we apply Newton’s law of motion to medicine, when CAR T-cell therapy effectively targets and kills cancer cells, an opposite reaction from the immune system causes treatment related-toxicities that can endanger the life of patients.
Many have called CAR T-cell therapy a “living drug;” a one-time therapy that appears to be sustainable within the body and targets cancer cell antigens if they are present. With only short-term follow-up data available, researchers have theorized that certain CAR T-cells could remain active in the body for years, decades, or even the rest of the patient’s life.
The problem is that once the initial infusion is given, current state of the art does not allow clinicians to control the dose or the timing of its activity. Any ability to control the activity of CAR T-cells within the body once they were administered would be the next great breakthrough in this emerging field.
Potentially Transformative Findings
Evan W. Weber, PhD, is a postdoctoral fellow in the Crystal Mackall Lab at the Stanford Cancer Institute. He told Cell Therapy Next that Mackall’s lab had been looking for ways to synthetically control CAR T-cell function by altering the CAR architecture. Weber said that the field is moving toward being able to precisely control CAR T-cell function and that Mackall’s lab has had some success in the area.
“Crystal and I sat down and talked about the idea of using an existing FDA-approved small molecule to achieve this,” he said.
Weber found studies published in 2008 that demonstrated how dasatinib (Sprycell; Bristol-Myers Squibb) repressed T-cell activation via the T-cell receptor. He said the studies showed that dasatinib completely suppressed T-cell activation and did so at low concentrations.
“This piqued my interest on whether tyrosine kinase inhibitors could have a similar effect on CAR T-cell activation,” Weber said. “Dasatanib is commercially available, and we got our hands on a lot of it and began experimenting. It became quickly obvious that it had a profoundly suppressive effect on CARs, as well as engineered and non-engineered T cells.”
When Weber first brought the idea of using dasatanib to control CAR T-cell function to Crystal L. Mackall, MD,director of the Stanford Center for Cancer Cell Therapy and associate director of the Stanford Cancer Institute, she admitted to being skeptical about its potential effectiveness.
“One of the curiosities about this story from my perspective is that we use dasatinib a lot in the clinic for chronic myeloid leukemia, and we don’t see clinical evidence of profound immunosuppression. So, when Evan showed me this literature it was a surprise to me and remains a surprise,” Mackall told Cell Therapy Next.
Weber and Mackall conducted their own preclinical study on whether dasatinib could be used to control CAR T-cell function.
“The truth is that it does; we have been able to replicate the previously published work demonstrating profound inhibition of T cell activation with dasatinib,” Mackall noted.
What Weber and colleagues found is that in mouse models, a 100 nM-dose substantially suppressed CD4+ and CD8+ CAR T-cell proliferation and that complete suppression was observed at a 1 µM-dose, but CAR T-cell function resumed within hours of the drug’s removal “demonstrating that dasatinib’s effects on CAR T-cell function are fully and rapidly reversible,” Weber and colleagues wrote in the published analysis.
“As we showed in our study, dasatinib can just shut it down,” Mackall commented, noting that based upon the evidence that dasatinib is well tolerated, this data suggested that excess cytokine production could be controlled with “quite acceptable” side effects.
“We think this is a great opportunity to repurpose a drug that is very well tolerated, and the hematology community is quite accustomed to using it.”
Weber added that as CAR T cells become more common and hopefully approved for targeting solid tumors, there continue to be toxicities associated with their use.
“We will need strategies to mitigate the toxicities,” he said. “Dasatinib is FDA approved and well tolerated in humans, in addition to being simple to use. We don’t necessarily need sophisticated engineering or synthetic biology; we can control CAR T cells with something that’s readily available. For these reasons, translating dasatinib could be transformative for the field in terms of controlling CAR T-cell therapy.”
Meanwhile, in New York...
Another team of researchers in the United States and Germany were actively looking for a CAR T on/off switch, or a “safety switch” as relayed by Theodoros Giavridis, PhD, who was at the time a graduate student in the Michel Sadelain Lab at Memorial Sloan Kettering Cancer Center.
Led by Katrin Mestermann, PhD, the group in the Michael Hudecek Lab at the University of Wurzburg in Germany originally showed that dasatinib could be used to pause CAR T-cell function, while Giavridis conducted the experiments that demonstrated the ability of dasatinib to significantly mitigate CRS toxicity as part of the Sadelain Lab at Memorial Sloan Kettering.
“Current approaches are largely focused on destructive safety switches, where CAR T cells are eliminated once the switch is triggered. Given the high cost of CAR T-cell therapy such approaches are financially precarious, and the patient would no longer benefit from the therapeutic activity of the infused CAR T cells,” he explained.
“Dasatinib offers the unique advantage to pause CAR T-cell function, ideally until side effects subside and later allow the CAR T cells to resume their pharmacological role by attacking the cancer, instead of destroying the CAR T cells altogether.”
Giavridis and colleagues published their own preclinical study earlier this year in Science Translational Medicine that detailed the use of dasatinib as a pharmacologic control switch for CAR T-cell function. The investigators demonstrated control of CAR T cells using a dose of 100 nM and the elimination of cytokine production that causes CRS in patients.
The study’s experimental mouse models used “extreme activation conditions” according to Giavridis, yet the administration of dasatinib at the onset of CRS prevented death in most mice.
“The activity of CAR T-cells is central to the development of these side effects and as such the field is in need of ways to control CAR T-cell activity,” Giavridis told Cell Therapy Next.
“Our research suggests that dasatinib is a highly promising clinical modality to control CRS. Moreover, it is an FDA-approved drug. Therefore, it should be relatively easy to bring this research to the clinic. If these results hold up in the clinic, we may soon be able to control CAR T-cell activity at will in patients and be able to quickly address side effects of CAR T-cell therapy,” he added.
“The importance and utility of this finding holds great potential for the field.”
Clinical Utility
Both Weber and Giavridis point out that finding a way to control CAR T-cell function using an independent agent will likely be far easier than the alternative of engineering CAR molecules themselves to produce less toxic side effects. The problem with single-dose “living drugs” is that you can’t adjust the dose or hold doses to manage toxicities, according to Francesco Paolo Tambaro, MD, PhD, a clinical research scientist for pediatric stem cell transplantation and cellular therapy at the University of Texas MD Anderson Cancer Center.
“Both studies provide in vitro and animal data that dasatinib can potentially reversibly modulate or decrease the activity of activated CAR T cells as a temporary on-off switch in these cells without killing or eliminating them,” Tambaro said. “This raises the possibility of a mechanism to modulate CAR T activity in patients as a way to prevent undesired and lethal toxicities due this extremely powerful treatment without eliminating the cells.”
Tambaro said the two studies demonstrate dasatinib’s effectiveness in controlling CAR T-cell function and should establish the basis for future clinical trials to test this mechanism. He told Cell Therapy Next that both studies were similar in methodology and show that dasatinib could control CAR T-cell activation, expansion, cytokine release, target cell killing and the associated toxicities. They also showed that the process was reversible.
However, the studies only indicated that CRS could be halted using this method and that whether immune effector cell-associated neurotoxicity syndrome (ICANS), the other common toxicity of CAR T-cell therapy, could be halted using dasatinib is unclear. Other issues for clinical research Tambaro pointed out include potential toxicities associated with dasatinib and if its administration would have any effect on the long-term effects of CAR T cells.
Michael Jain, MD, PhD, FRCPC, an assistant member for blood and marrow transplantation and cellular immunotherapy at Moffitt Cancer Center agrees with Tombaro that both studies are similar yet use slightly different experimental designs. In the end, however, in tandem they show that dasatinib can be used to shut off CAR T-cell function and after a drug wash-out period, recover function.
If the drug’s use was translated into clinical practice to control CAR T-cell function, then Jain sees it as extremely useful in potentially preventing the most severe cases of treatment-related toxicities.
“CAR T-cell therapy does carry with it some toxicity that can sometimes be quite important and severe,” Jain said. “These two studies provide a window into a drug that is already used in humans that may be able to help treat or decrease those toxicities, and I think it’s very exciting to have that as a possibility.”
Beyond its potential use to halt toxic side effects, Jain said it could be possible to use dasatinib in the design of new clinical trials that test control over the peak number of CAR T cells that are in a patient’s blood at any given time. By controlling the number of cells, he added, “we may be able to reduce some of the toxicity and just overall provide better outcomes for patients.”
Despite indicators of its usefulness in preclinical studies, Jain maintains a bit of healthy skepticism about the ability to translate the results into clinical practice.
“One of the differences between mouse models and human models is that people, generally speaking, have much more complexity in terms of the tumor microenvironments that the tumor lives in and different types of cells that live in the human body that get activated by CAR T cells,” he said. “What has not been shown in a clear way is even if you shut off the CAR T cells at some point, does that truly halt the inflammation that we’re seeing. ... Some of the things in these papers suggest that it might, but I have to admit that the mouse models are not perfect replications of what could happen in humans.”
Questions Remain
Mackall is optimistic about the ability to translate to the clinic what her colleagues at Stanford and Sloan-Kettering have demonstrated in preclinical studies.
“There is no reason to believe that dasatinib won’t suppress CAR T cells in humans. We know that when the drug achieves a concentration where it is active that it suppresses human CAR T cells,” she said.
“What we don’t know is what happens after the cells are turned off with dasatinib, and we need clinical data for this to determine what happens during that process,” Mackall observed. Questions like do the cells turn off for a long period, do they disappear, or do they retool so that the minute you remove dasatinib they come roaring back all need to be answered.
Yet, for all that is still unknown about how dasatinib will affect CAR T-cell function in humans, Mackall believes the preclinical research to date allows her to make one sound conclusion.
“For me there is enough information to recommend that patients with Philadelphia chromosome-positive acute lymphoblastic leukemia should not receive dasatinib when they are receiving CAR T-cell therapy,” she told Cell Therapy Next.
“It’s important that the clinician population realize that you don’t want to use dasatanib in concert with CAR T-cell therapy, as one clinician told me she had done when administering CAR T cells for a patient with Ph-positive ALL. Everything we know suggests that dasatinib will diminish the chance of responding to CAR T cells, and that’s a practical take-home point to note.”
Weber contends that another point of refinement lies in the proper dosing of patients to suppress CAR T-cell function, and that their point of reference to date has been the dosing given to patients with CML and ALL who are FDA-approved indications for dasatinib.
“I don’t know if that dosing strategy will lead to sustainable suppression of CAR T cells in humans so we may end up needing a higher dose of dasatanib for a shorter time, during the period you would expect to see CRS or neurotoxicity after infusion. That’s something that will have to be worked out in clinical research,” Weber said.
“To our knowledge, no formal plan for a clinical trial has been finalized yet, therefore we cannot be certain of the intended dosing of dasatinib,” Giavridis said, echoing the same concerns about dosing that Weber shared.
“Nonetheless, conversion of numbers from our mouse model to the clinic equates to doses of dasatinib that are given to leukemic patients that receive it as treatment. One would not anticipate additional side effects other than those already described for dasatinib,” he added.
Maybe what researchers in this area should be looking for is not an on/off switch, but rather something that allows them to ramp up or down CAR T-cell function as fast or slow as needed, much like a light dimmer switch.
“Although it is clear that you can suppress the function of CAR T cells using standard dosing of dasatinib, what is not clear is the pharmacokinetics,” Mackall said. “It could be that we end up ‘tuning’ CAR T cells with dasatinib — we may not want to turn them off all the way but perhaps dial back their potency at times. It may not be an all or nothing thing and that is something that will need to be worked out in clinical research.” – by Drew Amorosi
- References
- Mestermann K, et al. Sci Transl Med. 2019;doi:10.1126/scitranslmed.aau5907.
- Schade AE, et al. Blood. 2008;doi:10.1182/blood-2007-04-084814.
- Weber EW, et al. Blood Adv. 2019;doi:10.1182/bloodadvances.2018028720.
- Weichsel R, et al. Clin Cancer Res. 2008;doi:10.1158/1078-0432.CCR-07-4393.
- For more information:
- Theodoros Giavridis, PhD, can be reached at giavridis.theodore@gmail.com.
- Michael Jain, MD, PhD, FRCPC, can be reached at Michael.Jain@moffitt.org.
- Crystal L. Mackall, MD, can be reached at Stanford University, 265 Campus Dr. G3141A, MC5456, Stanford, CA 94305; email: cmackall@stanford.edu.
- Francesco Paolo Tambaro, MD, PhD, can be reached at University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 0087, Houston, TX 77030; email: FTambaro@mdanderson.org.
- Evan W. Weber, PhD, can be reached at Lokey Stem Cell Research Building (SIM1), Room G2105, 265 Campus Drive, Stanford, CA 94305; email: eweb@stanford.edu.
Disclosures: Giavridis reports being listed as co-inventor in a patent on CRS prevention filed by Memorial Sloan Kettering Cancer Center. Jain reports a consultant role for Kite/Gilead. Mackall is founder of and has a consultant role with Lyell Immunopharma and is a co-inventor on a patent for the use of dasatinib and other small molecules to modulate CAR T-cell function and mitigate CAR-associated toxicities. Tambaro reports no relevant financial disclosures. Weber reports a consultant role with Lyell Immunopharma and is co-inventor on a patent for the use of dasatinib and other small molecules to modulate CAR T-cell function and mitigate CAR-associated toxicities.