‘Basic’ research leads to potential breakthrough to enhance CAR-T for solid tumors
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Researchers who identified proteins that influence T-cell formation have leveraged their discovery to develop a process that boosts the efficacy of chimeric antigen receptor T-cell therapy for solid tumors.
Preclinical studies by investigators at St. Jude Children’s Research Hospital, results of which appeared in Nature, showed the protein complex canonical Brg1/Brg‐associated factor (cBAF) interacts with the transcription factor c‐Myc to influence T-cell formation during the cell division process.
Daughter cells with high cBAF and c‐Myc concentrations became effector T cells, whereas daughter cells with lower concentrations of cBAF and c-Myc became memory T cells, researchers found.
Effector CAR T cells work quickly and then die, but memory CAR T cells have greater longevity and generate future effector cells while simultaneously attacking tumor cells, according to Douglas R. Green, PhD, chair of the immunology department at St. Jude.
The findings — and their potential impact on developing more effective CAR T cells — are the result of concurrent yet independent research from different departments at the institution.
“This was an example of the productive convergence that can occur when scientists trust each other to discuss our progress and are open ... to collaboration,” Green told Healio.
Investigators synthesized and tested the results in preclinical models of sarcoma and glioma, but Green said there is no reason to doubt the findings may help enhance CAR T-cell efficacy for other solid tumors or hematologic malignancies.
Green spoke with Healio about what research has shown so far and how investigators are working to apply what they have learned to the use of CAR T cells.
Healio: Can you describe the origin for the approach you used to enhance CAR T-cell efficacy?
Green: Ao Guo, PhD, working in my laboratory, generated evidence that a component of cBAF directs the fate of activated CD8 T cells away from the memory response. He presented his data at our weekly departmental ‘research in progress’ meeting. My colleague, Hongbo Chi, PhD, saw these data and told us his trainee, Hongling Huang, PhD, had discovered cBAF components in a screening he conducted to detect proteins that limit T-cell memory. We all began our fruitful collaboration that day.
Healio: Can you provide insight into how you inhibited the cBAF complex in your experiments and how this might be translated into human use?
Green: Our experiments showed that cBAF acts early after T-cell activation, having effects around the time of the first T-cell division. Deleting cBAF components rendered CD8 T cells more prone to generate memory T cells, and we found that these engineered cells had greatly improved antitumor responses.
We identified an inhibitor of cBAF reported in the literature and activated T cells in the presence of the inhibitor for the first 48 hours, covering the timing of the first division. We once again found that this division generated more memory cells — using either mouse or human T cells. Because CAR T cells are generated by first activating them to proliferate and then transducing them with the CAR construct, we hypothesized that transient treatment with a cBAF inhibitor would result in more effective CAR T cells. To address this question, we formed a collaboration with Giedre Krencuite, PhD, an expert on CAR T cells with St. Jude’s department of bone marrow transplantation and cellular therapy.
Healio: What did the results of your preclinical research show?
Green: We were thrilled to discover that transient treatment of activated CD8 T cells with a cBAF inhibitor — prior to generating CAR-T cells — resulted in improved longevity of the cells in mice and improved anticancer responses. We similarly found that activating human T cells in the presence of the cBAF inhibitor for the first 48 hours improved memory T-cell generation, and these cells showed greater longevity when transferred into immune-compromised animals.
Healio: Do you believe these findings have the potential to impact the future of clinical care for solid tumors?
Green: We are exploring the use of this treatment for the generation of human CAR-T cells. We are working with Stephen Gottschalk, MD, chair of the department of bone marrow transplantation and cellular therapy, to eventually translate our findings to the clinic.
However, there are a number of hurdles to overcome. First, we would like to identify additional inhibitors of cBAF that might be amenable to production for clinical use. Second, the most promising CARs for targeting solid cancers must be identified and methods employed to more effectively ensure that they specifically target the tumors. Finally, we will have to optimize our use of cBAF inhibitors for this application.
All of these hurdles can be overcome. A great advantage of our approach is that the drug never goes into the patient, but instead is only used in the generation of the CAR T cells. This avoids any potential adverse effects of the drug on other cell types, including the tumor.
Healio: Is there anything else you feel is important to emphasize?
Green: This is an example of how discovery research — which some would call ‘basic’ — reveals fundamental features of biology that can lead to clinical applications. We did not set out to identify methods to improve CAR T-cell therapy but, instead, explored the cell and molecular biology of early events in T-cell activation that influence eventual cell fate. As always, we ‘followed the data’ to take us to where we are today. We never know where a discovery may lead. ... By fiercely addressing questions about biology, and applying the answers, we advance our important mission.
Reference:
Guo A, et al. Nature. 2022;doi:10.1038/s41586-022-04849-0.
For more information:
Douglas R. Green, PhD, can be reached at St. Jude Children's Research Hospital, 262 Danny Thomas Place, MS 351, Room E7050, Memphis, TN 38105-3678; email: douglas.green@stjude.org.
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