CAR-T treatments like Novartis’ Kymriah have proven effective in some B-cell-driven cancers, with one notable exception: chronic lymphocytic leukemia (CLL). Now, researchers at the University of Pennsylvania, which pioneered the CAR-T technology that formed the backbone of Kymriah, are proposing a new method for overcoming CAR-T resistance in CLL.
The Penn team demonstrated that they could improve the function of CAR-T cells by inhibiting bromodomain and extra terminal (BET) proteins. Blocking BET helped combat “T cell exhaustion,” a well-known phenomenon that prevents engineered CAR-T cell treatments from fully attacking CLL, they reported in the Journal of Clinical Investigation. Novartis, which has a licensing arrangement with Penn, was one of the backers of the study, along with the National Cancer Institute and several other groups.
CAR-T treatments, which are made from patients’ own immune cells, have been about 80% effective in acute lymphocytic leukemia (ALL), often curing advanced forms of the disease. But only a small fraction of CLL patients have responded well to CAR-Ts in clinical trials.
Newly diagnosed CLL patients are typically treated with aggressive chemotherapy, which can cause T cells to become exhausted. Working on the assumption that the exhausted T cells may be the reason behind CAR-T resistance, the Penn team studied CAR-T cells from several CLL patients who had been treated with them.
In those cells, the researchers showed that BET turns down the expression of the CAR (chimeric antigen receptor). When they inhibited BET with a small-molecule drug called JQ1, T-cell exhaustion dropped and they were able to increase the production of CAR-T cells.
What’s more, the JQ1 boosted levels of certain cytokines and chemokines—proteins made by immune cells that previous studies had shown were key to the success of CAR-T in some CLL patients.
So how could the Penn discovery be applied to CAR-T development for CLL? The researchers suggested that JQ1 could be used to improve the engineering and expansion of CAR-T cells that are made for CLL patients, many of whom will be starting the treatment process after their T cells have been worn down by chemotherapy.
“Treating these ‘war weary’ T cells during the CAR-T cell engineering process has the potential to boost responses,” said senior author Joseph Fraietta, Ph.D., an assistant professor of microbiology at Penn, in a statement.
Combating tired T cells is a major area of research in immuno-oncology. Earlier this year, a Moffitt Cancer Center team reported a link between non-responders to Gilead Sciences’ CAR-T therapy Yescarta in diffuse large B-cell lymphoma and high expression of genes that control tumor interferon signaling. They suggested the discovery could inform strategies for preparing patients’ immune cells prior to CAR-T therapy.
In 2019, another group of Penn researchers reported their finding that a protein called TOX orchestrates exhausted T cells—a discovery they suggested could inspire new immuno-oncology treatments.
Fraietta’s team at Penn is planning further studies to better elucidate how immune pathways contribute to JQ1’s effects on CAR-T cells.