Genetically engineered CAR T cells that evade a key immunosuppressive signal in tumors may help extend the reach of cell therapies to solid cancers, according to a new study from Ludwig-Maximilians-Universität München.
The research shows that disabling two receptors used by tumors to suppress immune activity enables CAR T cells to remain active within the tumor microenvironment, improving their ability to control solid tumors in preclinical models.
CAR T therapies have transformed treatment for certain blood cancers, but success against solid tumors has remained limited. One major obstacle is the tumor microenvironment, where signaling molecules can dampen the activity and persistence of therapeutic T cells.
Previous work by the LMU team identified prostaglandin E2 (PGE2) as a key mediator of this suppression. In the new study, researchers used CRISPR–Cas9 gene editing to knock out the two receptors through which PGE2 suppresses T cells – EP2 and EP4 – in therapeutic CAR T cells. The modified cells continued to expand and function in PGE2-rich tumor settings, unlike unmodified counterparts.
The approach improved tumor control in mouse models of pancreatic cancer, melanoma, and mesothelioma, and also enhanced anti-tumor activity in patient-derived tumor samples from pancreatic, colorectal, and neuroendocrine cancers.
Mechanistically, the benefit appeared to stem less from increased killing capacity than from improved persistence of the engineered cells within tumors. The team reports that EP2/EP4-deficient CAR T cells showed stronger intratumoral expansion and prolonged survival in vivo, suggesting that protection from PGE2 signaling helps sustain therapeutic pressure in solid tumors.
“However, we are gaining a better understanding of the underlying molecular mechanisms all the time,” said Sebastian Kobold in the team’s press release. His group had previously shown that PGE2 in the tumor microenvironment suppresses T-cell function by binding receptors on the cell surface.
The researchers suggest the strategy could first strengthen CAR T therapy in lymphoma – where the approach is already established – before being tested in solid tumors.
“Soon it will be possible to test our approach in clinical studies,” said Janina Dörr, lead author of the study. “According to our findings, there is a good chance that therapy with silenced PGE2 will be considerably more successful,” added Kobold.
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