MedPacto drug clears 75% of aggressive pancreatic tumors in mice and leaves lasting immune memory

A team led by Dr. Seong-Jin Kim at MedPacto, Inc. in Seoul, Korea, has described an experimental TGF-β blocker that, in mice, cleared aggressive pancreatic tumors, stopped breast cancer from spreading and left long-lasting immune memory, according to newswise.com. The study was published in Cancer Cell. newswise.comnewswise.comnewswise.comOpen source ↗ Co-author John J. Letterio, MD, PhD, directs programs at University Hospitals Rainbow Babies & Children's Hospital and Case Western Reserve University in Cleveland, Ohio.

Many solid tumors, including cancers of the pancreas, breast, colon and lung, are protected by a dense wall of scar-like tissue that keeps T cells out. This is a major reason why immunotherapy drugs help only a minority of people with solid tumors. Tumors release the signaling molecule TGF-β, which directs nearby support cells to build fibrous tissue and suppresses immune cells. Drugs that block TGF-β throughout the body have disappointed in clinical trials: safe doses do not block enough of it inside the tumor, and higher doses disrupt its normal roles in healthy tissue.

Delivery to the tumor

The researchers 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 target was found at high levels in mouse models of breast, colon, 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. This signal converted the tumor's own support cells and nearby immune cells into cells that display pieces of the cancer to the immune system. The reprogramming was seen in both pancreatic tumors and melanoma. newswise.comnewswise.comnewswise.comOpen source ↗

Results in mice

The drug worked in three mouse models of pancreatic cancer. In one aggressive model, tumors disappeared in 75% of treated mice, and seven of eight were still alive 270 days after treatment ended. In a highly metastatic model of triple-negative breast cancer, 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.

Mice that cleared their tumors 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 these 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 other standard therapies. newswise.comnewswise.comnewswise.comOpen source ↗