Bringing CAR-T to solid tumors with help from alpacas

CAR-T therapies made from individual patients’ immune cells have revolutionized the treatment of some blood cancers, but they’ve been difficult to translate to solid tumors. Part of the problem is tumors are protected by proteins that prevent immune cells from being able to wage an effective attack.

Scientists at Boston Children's Hospital and the Massachusetts Institute of Technology—with some assistance from alpacas—have devised a way to break through that barrier. Using "nanobodies" inspired by a type of antibody found in alpacas, the team built CAR-T cells that can recognize specific proteins that protect tumors. They described their work in the journal Proceedings of the National Academy of Sciences.

Alpacas make antibodies in their blood that consist of only two heavy protein chains—a smaller version of human antibodies, which are made of up two heavy and two light chains. The researchers took chiseled down alpaca antibodies called nanobodies, trained them to recognize and target certain protective proteins that surround tumors, and attached them to CAR-T cells.

The CAR-Ts were able to target one protein called EIIIB, which is found in the blood vessels that feed tumors, and another, PD-L1, an immune "checkpoint" that prevents T cells from attacking cancer. When they tested the cells in mouse models of colon cancer and melanoma, they found tumor growth was slowed and survival improved, according to a statement.

Nanobodies, which are also found in the blood of camels and llamas, have been of great interest in the pharmaceutical industry since they were discovered 30 years ago. Sanofi made a splash last year when it bought out nanobody developer Ablynx for $4.5 billion—an investment that recently paid off with the FDA approval of Cablivi to treat acquired thrombotic thrombocytopenic purpura.

In November, Scripps Research Institute scientists described how they made a nanobody-based universal flu vaccine by immunizing llamas and then isolating broadly neutralizing single-domain antibodies from their blood. A team at the University of California, Riverside is developing camel-inspired monoclonal antibodies that bind to metalloproteinases, enzymes that can play a role in cancer, asthma, multiple sclerosis and other diseases.

The MIT-Boston Children’s team is investigating several uses for its CAR-T cells, said senior investigator Hidde Ploegh, Ph.D., in the statement. Destroying the blood supply to tumors by targeting EIIIB, for example, "could perhaps improve the delivery of other things that might have a harder time getting in," said Ploegh an immunologist at Boston Children’s. "I think we should look at this as part of a combination therapy."

One possibility, he said, is to use the nanobodies to carry immune-boosting cytokines or radiation directly to tumors. The team plans to continue investigating the nanobody-based CAR-T cells in other tumor types, including pancreatic and bile duct cancers.

by Arlene Weintraub

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