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Targeting Tumor-Promoting Cells: Lipid Nanoparticles Before CAR T Success in Pancreatic Cancer

Often diagnosed when surgery is no longer an option, pancreatic cancer is one of the most difficult cancers to treat and has the lowest survival rate among major malignancies.Like many solid tumors, the most common type of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), is surrounded by a desmoplastic matrix—containing connective tissue, structural proteins, and cancer-associated fibroblasts.There is a dense barrier of specialized cells called (CAFs) - which also reduce the immune response.

Importantly, this microenvironment has limited the use of chimeric antigen receptor (CAR) T-cell therapy, a form of cancer immunotherapy that has achieved significant success in the treatment of blood cancers such as lymphoma, leukemia and multiple myeloma.

Revamping CAR T delivery using LNP

Now, researchers led by Ellen Puré of the School of Medicine have used lipid nanoparticles (LNPs) - small particles that can be an effective drug delivery system - to make CAR T cells directed at CAFs in vivo to "eliminate" this barrier in a preclinical model.These findings, published in Cancer Immunology Research , pave the way to a safer, easier, and more cost-effective way to use CAR T cell therapy to treat solid tumors.

"The expansion of CAR T has been huge," says Pure, professor and director of the Pennsylvania Veterinary Cancer Center."But they're really only successful in treating tumors."

Conventional CAR T cell therapy is also complicated to administer, she notes, requiring the removal, engineering and recycling of a patient's T cells.The process also often requires lymphodepletion, which temporarily reduces the number of immune cells that can fight or block the infused CAR T cells.In comparison, LNP-based approaches may be simpler and cheaper to deliver and promote in other situations.Has shown promising results.

How targeted nanoparticles arm T cells.

LNPs act as tiny delivery vehicles, carrying CAR instructions directly to the patient's T cells so that the CAR is produced in the patient's body, explained Khulud Bajbooz, a senior researcher at Pure's laboratory.

The group used LNPs to equip T cells to target fibroblast-activated proteins, or FAP, because they are present at high levels in a subset of cancer-related tumors (cells known to be important for PDAC development)."It's like you're equipping a T cell with a laser-focused approach," Bajbouj says.

The researchers chose to focus on FAP because previous studies targeting these cells using traditional CAR T have slowed tumor growth, Purée said.

Surprising results in preclinical pancreatic tumors

In this study, they found that a single dose of targeted LNPs (tLNPs) in a preclinical model of PDAC was as good, if not better, at inhibiting tumor growth than the conventional method.

"Usually less than 10% of the T cells that enter the tumor are armed," says Puré."But when we do this with the tLNPs, we find that 40 to 60% of the T cells express the CAR."

These armored T cells are present for a short time compared to what is seen in the conventional approach, he says."It's as if the whole army just came in, all at once, instead of in waves."

And the result of this surprised even the researchers."We expected it would eliminate FAP-positive cells," Puré said."But we didn't expect that the desmoplastic matrix would just dissolve."

Opening the door to integrative medicine

This result makes it possible to use this method with other treatments to improve the effectiveness of solid tumors, said Bajbouj.

"If you're not at the table, you can't have a conversation, right?"Puré says, adding that these tLNPs could be used to test new treatments or even CAR T therapies that have not yet been proven to work."Once the door is open, a lot of treatments can go in and do well."

Their data also suggest that this approach might be effective for treating metastatic cancer, which, she adds, is what kills most cancer patients.

Potential implications beyond pancreatic cancer

"FAP-positive cells can facilitate the spread of tumor cells to other sites, helping them survive in transit and promoting the formation of metastatic lesions," says Puré.Tumor cells also send signals to activate FAP in these other sites, which he compares to preparing garden beds before planting seeds.

"We think these cells are very important in the metastatic stage," he says."If we target this, we know we will have a greater impact."

Ultimately, they believe that using LNPs to target FAP-positive cells may have the potential to treat other conditions such as fibrosis, autoimmunity, arthritis, or even wound healing.

"Patients will not be put on conventional CAR T-cell therapy for all these indications," says Puré."But the tLNP mRNA approach may be more acceptable from a risk-benefit perspective."

Khuloud Bajbouj et al., FAP-CAR mRNA targeted lipid nanoparticle delivery enables in vivo T-cell engineering against pancreatic tumors, Cancer Immunology Research (2026).DOI: 10.1158/2326-6026-irc.

Provided by the University of Pennsylvania.