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Preclinical research findings from UNC Lineberger Comprehensive Cancer Center identified a combination of three different drugs that can be used to boost immunotherapy to fight cancer. This finding may have a significant impact on improving the production of chimeric antigen receptor-T cells for clinical use.

The research findings appeared Jan. 8 in鈥�. The paper鈥檚 two corresponding authors are Lineberger researchers and postdoctoral research fellow Yang Xu. Feifei Song, another Lineberger postdoctoral research fellow, is the first author.

CAR-T cell immunotherapy involves harvesting immune-system T cells from a patient and genetically re-engineering them in the lab to recognize targets on the surface of cancer cells when they are reinfused into patients. Patients treated with certain types of CAR-T cells can have significant responses to their cancer, particularly when the re-engineered cells contain a subset of immune cells identified as T-memory stem cells.

鈥淐AR-T cells produced in the lab for reinfusion can be extremely different from one patient to another, and the lack of certain types of cells in the end product can significantly reduce the capacity of these cells to persist long term,鈥� said鈥疍otti, professor of microbiology and immunology at UNC School of Medicine and co-leader of the Lineberger immunology research program. 鈥淥ur study demonstrates that the addition of the drugs we have identified during the re-engineering process allows the preservation of a critical cell subset responsible for long-term persistence.鈥�

The researchers identified several enzymes called kinases that are involved in the enrichment of CAR-T cells that are like T-memory stem cells. The identification of the kinases then allowed the scientists to conduct a sophisticated screening process to search for kinase-inhibiting drugs that preserve these cells in re-engineered CAR-T cells generated from both healthy donors and patients with chronic lymphocytic leukemia.

Since targeting a single signaling pathway often triggers defensive mechanisms in cancer cells, the researchers thought that the use of several kinase inhibitors that target multiple, nonoverlapping pathways might bypass that mechanism and achieve greater enrichment of T-memory stem cells in CAR-T cell products, improving anti-tumor activity.

The investigators were correct.

One of their most striking findings was the inability of a lone kinase inhibitor to increase the frequency of certain CAR-T cells that are like T-memory stem cells. In sharp contrast, the three-drug kinase inhibitor combination consistently increased the frequency of these cells in both healthy donors and patients with chronic lymphocytic leukemia.

鈥淭he T cells in these patients are really dysfunctional cells. The strategy we propose is not tailored to blood-borne malignancies but is a general concept applicable to CAR-T cell manufacturing for all diseases,鈥� Dotti said. The study also shows the advantages of using drugs instead of gene-targeted therapies that haven鈥檛 been as effective in enriching these cells.

Dotti and his colleagues said more research is needed to determine how the kinase inhibitors actively drive the differentiation of T-memory stem cells before the experimental drug combination can be studied in a clinical trial. But they believe that their kinase inhibitor combination could be rapidly integrated into the manufacturing of other T-cell products used to fight cancer.

The research was supported by grants from the National Cancer Institute and the University Cancer Research Fund. A complete listing of authors, funding sources and disclosures is available in the published paper.