Manipulating T-cell fate to improve CAR-T therapy in solid tumors

Manipulating T-cell fate to improve CAR-T therapy in solid tumors

CAR-T therapy that modifies a patient’s immune cells to target cancer has shown strong efficacy in blood cancers. But the engineered T cells’ lack of persistence represents one challenge that has prevented their success against solid tumors. Scientists at St. Jude Children’s Research Hospital have now identified a mechanism that they say could help CAR-T cells last longer in the body and thus better fight solid cancers.

An interaction between the protein c-Myc and the protein complex cBAF early in T-cell activation affects T-cell fate, the team described in a new study published in Nature.

Fine-tuning this interaction could let naïve T cells—upon activation by a tumor antigen—preferentially differentiate toward long-lasting memory T cells rather than the fast-acting but short-living T effector cells, the team showed. Doing so markedly improved the efficacy of CAR-T cells in a mouse solid tumor model, the team reported.

“Our work extends from the basic biology of T lymphocytes to a possible application in the clinic, with an exploration of deep molecular mechanisms along the way,” co-corresponding author Doug Green, Ph.D., said in a statement.

Co-corresponding author Hongbo Chi, Ph.D., has been studying how a T cell becomes a memory cell. In this study, the team used the genetic screening tool CRISPR to look for molecular inhibitors of antigen-specific memory T-cell generation.

That led them to several components of the cBAF complex. Deleting cBAF promoted the generation of memory precursor cells versus terminal effector cells, the team found. Further analysis showed that cBAF promoted the expression of genes associated with effector cell function.

While effector T cells are important in an initial anti-tumor response, most of them die afterward. By comparison, the memory precursor cells can give rise to self-renewing memory T cells, which can offer long-term protection when they encounter the cancer-related antigen again in the future.

The CRISPR screen also showed reduced c-Myc in memory precursor cells than in terminal effector cells. Green and colleagues had previously found that the c-Myc in a parental T cell can be sorted differently during its division into two daughter cells. So the team decided to examine the relationships between c-Myc and cBAF at early time points of T-cell activation.

The team found that cBAF and c-Myc physically interact to remodel the DNA-protein complex chromatin in activated CD8+ T cells. Daughter cells with high cBAF and c-Myc showed a cell fate trajectory toward effector T cells, whereas those with low expressions tend to become memory T cells.

Armed with the knowledge, the scientists tested the effect of cBAF inhibition during CAR-T cell activation in a mouse model bearing B7-H3-positive bone tumors. Turns out, B7-H3 CAR-T cells generated from T cells that had been transiently treated with a cBAF inhibitor showed markedly enhanced tumor control compared with CAR-T cells derived from untreated T cells.

The team also verified the effect on human CD8+ T cells. Treatment of the cBAF inhibitor early on was necessary and sufficient to promote the generation of cells with markers of long-lived memory cells and reduced the number of effector cells. Once transferred into mice, the cBAF inhibitor-treated T cells persisted longer.

Scientists have been looking for ways to help CAR-T cells survive longer and keep proliferating to make them better cancer treatments. For example, a team at Curie Institute in France recently found that crippling SOCS1 in CAR-T cells could improve the persistence and function of the cells.

Findings from the current study “indicate that transient inhibition of cBAF function during T cell activation may improve CAR-T therapy for human cancers,” the St. Jude scientists wrote in the study.

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