Researchers led by Ellen Puré of the School of Veterinary Medicine announced on Mar. 31 that they have used lipid nanoparticles (LNPs) to help chimeric antigen receptor (CAR) T cells overcome barriers in treating pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer. The findings were published in Cancer Immunology Research.
Pancreatic cancer is known for being difficult to treat and has one of the lowest survival rates among major cancers. One challenge is a dense barrier called the desmoplastic matrix, which shields tumors and suppresses immune responses, making therapies less effective.
The team used LNPs as delivery vehicles to equip T cells with instructions targeting fibroblast activation protein (FAP), found at high levels on certain cancer-associated fibroblasts that contribute to tumor progression. "It is like you are equipping T cells with a laser-focused approach," said Khuloud Bajbouj, a senior research investigator in Puré's lab.
A single dose of targeted LNPs was found to be as effective or better at inhibiting tumor growth than conventional CAR T cell approaches in preclinical models. "It's usually less than 10% of all the T cells that go into the tumor that are armed," said Puré. "But when we do this with the tLNPs, we're finding 40 to 60% of the T cells are expressing the CAR." She added that these modified T cells act quickly: "It's like the entire army just comes in, all at once, instead of in waves." The researchers were surprised by how effectively this method dissolved the protective matrix around tumors: "We expected it to get rid of the FAP-positive cells," said Puré. "But we didn't expect the desmoplastic matrix to just melt away."
This new approach could also be combined with other treatments such as chemotherapy or immunotherapy and may be useful against metastatic cancer as well. "FAP-positive cells can facilitate tumor cell spread to other places... We think these cells are very important in the metastatic phase," said Puré.
Puré concluded that targeting FAP-positive cells using LNPs might also help treat conditions beyond cancer, including fibrosis and autoimmunity: "You are not going to put patients through conventional CAR T cell therapy for all of these indications... But the tLNP mRNA approach may be more palatable from a risk-benefit perspective."
