MedPacto drug opens solid tumors to T cells and clears pancreatic tumors in mice

A team led by Seong-Jin Kim at MedPacto, Inc. in Seoul, Korea, describes an experimental drug that breaks down the dense, scar-like barrier of solid tumors from the inside and lets T cells enter. The study was published in Cancer Cell and covered by news-medical.net news-medical.netnews-medical.netnews-medical.netOpen source ↗. In mice, the drug cleared aggressive pancreatic tumors, stopped breast cancer from spreading and left the animals with long-lasting immune memory. Co-author John J. Letterio works at University Hospitals Rainbow Babies & Children's Hospital and Case Western Reserve University.

TGF-β blockade aimed at the tumor

Tumors release TGF-β, which directs nearby support cells to build fibrous tissue and suppresses immune cells. Blockers that act throughout the body have disappointed in clinical trials: safe doses do not block enough TGF-β in the tumor, and higher doses disrupt its normal roles in healthy tissue.

The team engineered a blocker, FEBP-sTβRII, with a tag that binds a form of fibronectin that is abundant in tumors but rare in healthy adult tissue. The authors found this target in mouse models of breast, lung, liver, prostate, pancreatic and brain cancers and melanoma, and in many human tumor types. The drug gathers in the tumor and stays there for days. The same blocker without the tag had little effect on tumors and changed the activity of 693 genes in the blood, compared with 25 for the targeted drug.

Once the barrier loosened, T cells moved into the tumor and released interferon-gamma. It converted the tumor's support cells and nearby immune cells into cells that display pieces of the cancer to the immune system. The authors saw this reprogramming in pancreatic tumors and melanoma news-medical.netnews-medical.netnews-medical.netOpen source ↗.

Results in mice

The drug worked in three pancreatic cancer mouse models. In one aggressive model, tumors disappeared in 75% of treated mice, and seven of eight were alive 270 days after treatment ended. In a highly metastatic triple-negative breast cancer model, it slowed tumor growth, prevented spread to the lungs and extended survival, while standard immunotherapy and untargeted TGF-β blockers gave little or no benefit. Added to the anti-PD-1 drug, it nearly eradicated pancreatic tumors that resist that drug alone.

Cured mice rejected the same cancer when it was reintroduced months later, and many also rejected bladder and lung tumors they had never encountered. T cells from cured mice protected cancer-free mice against bladder cancer.

A version of the drug designed for humans has entered safety testing, with clinical trials planned for 2027 in patients with solid tumors refractory to standard therapies news-medical.netnews-medical.netnews-medical.netOpen source ↗.