Boosting BACH2 blocks CAR-T exhaustion
Original story from University of Texas (UT) Southwestern Medical Center (TX, USA).
Boosting levels of the protein BACH2 could improve CAR-T therapies’ effectiveness against cancer.
UT Southwestern Medical Center researchers have discovered that increasing the levels of a protein called BACH2 makes engineered cancer-fighting immune cells behave more like stem cells, improving their therapeutic effectiveness. The findings suggest new strategies for improving the efficacy of these immune cells, known as chimeric antigen receptor (CAR)-T cells.
“Using a mouse model of solid cancer, we found that programming CAR-T cells to acquire stem-like properties during manufacturing significantly enhances their antitumor activity. This fine-tuning of CAR-T cells may represent a powerful strategy to overcome key barriers in solid tumor immunotherapy,” said Tuoqi Wu, who co-led the study with Chen Yao. Both researchers are Assistant Professors of Immunology and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.
CAR-T cells have been approved by the Food and Drug Administration as an anticancer therapy since 2017. These cells are created by collecting a cancer patient’s own T cells, then genetically engineering them to fight that patient’s specific cancer. Although CAR-T cells have shown enormous promise in fighting blood cancers, such as leukemias and lymphomas, they offer long-lasting remission in only a subset of cases. Additionally, CAR-T cells are largely ineffective at fighting solid tumors.
This inefficacy mostly stems from a phenomenon known as exhaustion, Wu explained. Constant stimulation of CAR-T cells by antigens on cancer cell surfaces eventually leaves them unable to fight cancer cells, proliferate, or respond to immune checkpoint-inhibiting drugs. They also show markers of a dysregulated metabolism and ultimately die. Understanding why exhaustion develops will be key to making CAR-T cells a more effective therapy for all cancers.
Several years ago, Drs Wu and Yao found an important clue in another study they performed examining T-cell exhaustion in chronic viral infections. There, T cells had a range of propensities to become exhausted. But those least likely to become exhausted had properties more akin to stem cells. Those with higher “stemness” produced more of a protein known as BACH2.
To see if the same was true in CAR-T cells, the researchers developed these cells from mice. Much like in the previous study, cells with higher expression of the gene for BACH2 also maintained more stem-like qualities than those with lower expression. Cells with more BACH2 were also less likely to become exhausted and fought off leukemia better than those with less BACH2. The researchers found similar results when they looked at BACH2 expression in human CAR-T cell samples.
Capitalizing on these findings, the researchers generated mouse CAR-T cells that produced varying levels of BACH2. CAR-T cells that produced the highest levels of BACH2 remained the most stem-like and were the best at resisting exhaustion while growing in petri dishes. Using a different strategy, the researchers temporarily boosted the amount of BACH2 that CAR-T cells produced during their manufacture, then infused them into a mouse model of neuroblastoma, a type of solid malignant tumor that develops in nerve cell precursors. This tweak significantly improved the cells’ cancer-controlling ability compared with typical CAR-T cells, restricting the tumors’ growth.
Drs Wu and Yao said their study suggests that increasing BACH2 production in CAR-T cells could offer a viable technique to help them resist exhaustion and fight both blood and solid tumor cancers. They hope to eventually test this strategy in clinical trials.
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