Researchers have found a combination of three drugs that boosts the production of CAR-T cells, a type of immunotherapy for cancer. This could enhance CAR-T cell production for use in clinical settings. The study highlights the significance of T-memory stem cells (TSCM), which are associated with stronger and longer-lasting cancer responses. The results suggest that using drugs may be more beneficial than gene-targeting methods for increasing TSCM-like cells, as gene-targeted therapies have often not been very effective in this area.
A preclinical study from the University of North Carolina Lineberger Comprehensive Cancer Center discovered a mix of three different drugs that can create stronger CAR-T cells (chimeric antigen receptor-T cells) to combat cancer. This development holds great promise for enhancing CAR-T cell production for clinical applications.
CAR-T cell therapy involves extracting T cells from a patient, modifying them in the lab to identify cancer cell markers, and then reinfusing them back into the patient. Patients receiving certain CAR-T therapies can experience substantial responses, particularly when the modified cells contain T-memory stem cells (TSCM).
The research findings were published on January 8 in Nature Immunology.
“The CAR-T cells produced in the lab can significantly differ from one another, and not having specific cell types in the final product can greatly hinder their long-term effectiveness,” explained Gianpietro Dotti, MD, a professor of microbiology and immunology at UNC School of Medicine and co-leader of the UNC Lineberger immunology research program. “Our study shows that incorporating the drugs we identified during the modification process helps keep a vital cell subset that is crucial for long-lasting effects.”
Dotti and Yang Xu, PhD, are the corresponding authors of the study, with Feifei Song, PhD, a postdoctoral research fellow at UNC Lineberger, as the lead author.
The team used laboratory and mouse model experiments to pinpoint several enzymes known as kinases (ITK, ADCK3, MAP3K4, and CDK13) that play a role in boosting TSCM-like CAR-T cells. Notably, ADCK3 and MAP3K4 emerged as promising new targets within T cells, indicating that further investigation into their functions and signaling mechanisms could offer insights into how T cells evolve to perform essential immune duties.
Finding these kinases enabled the researchers to conduct an advanced screening for drugs that inhibit these kinases and maintain TSCM-like cells in CAR-T cells produced from both healthy individuals and patients with chronic lymphocytic leukemia (CLL).
The researchers realized that targeting a single signaling pathway might trigger counteraction mechanisms in cancer cells. Therefore, they hypothesized that using multiple kinase inhibitors targeting various, non-overlapping pathways could evade such compensatory responses and result in a greater presence of TSCMs in CAR-T cell products, thereby enhancing anti-tumor effectiveness.
The results supported their hypothesis.
A key finding was that a single kinase inhibitor was ineffective in increasing certain TSCM-like CAR-T cells. In contrast, the three-drug cocktail significantly boosted the prevalence of TSCM-like CAR-T cells in both healthy donors and CLL patients who had particularly impaired T cells.
“We focused on CLL for our tests because the T cells from these patients are notably dysfunctional. The approach we propose isn’t just for blood-related cancers but is a broad concept that can be applied to CAR-T cell production across various diseases,” said Dotti. “Our study further illustrates the benefits of pharmacological methods over genetic ones for enhancing TSCM-like cells, as many gene-targeting therapies have not been highly successful in this field.”
Dotti and his team noted that more research is needed to understand how the kinase inhibitors promote TSCM differentiation before the experimental drug mix can enter clinical trials. However, they believe that their cocktail could be rapidly adopted into the production of other T-cell products, such as tumor-infiltrating lymphocytes, which are also employed in cancer treatment.
