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In 1989, two undergraduate students from the Free University of Brussels were invited to test the frozen blood serum of camels and came across a previously unknown type of antibody. It was a miniaturized version of a human antibody, composed only of two heavy protein chains, rather than two light chains and two heavy chains. As they finally reported, the presence of antibodies was confirmed not only in camels, but also in llamas and alpacas.
Fast forward 30 years. In the newspaper PNASThis week, researchers at the Boston Children's Hospital and MIT have shown that these mini-antibodies, reduced to the manufacture of nanobodies, could help solve a problem in the field of cancer: to ensure that T-cell based CAR therapies work in solid tumors. |
Highly promising for blood cancers, chimeric antigen receptor (CAR) T-cell therapy genetically modifies a patient's own T cells to make them more effective in attacking cancer cells. The Dana-Farber / Boston Children's Blood Cancer and Blood Cancer Treatment Center currently uses CAR T cell therapy for the treatment of relapsed acute lymphocytic leukemia (ALL), for example.
But CAR T cells did not eliminate solid tumors. It has been difficult to find cancer-specific proteins on solid tumors that can serve as safe targets. Solid tumors are also protected by an extracellular matrix, a network of supporting proteins that acts as a barrier, as well as by immunosuppressive molecules that weaken T cell attack.
Rethinking CAR T cells
That's where nanobodies come in. For two decades, they remained largely in the hands of the Belgian team. But that changed after the patent expired in 2013.
"Many people have started playing the game and have begun to appreciate the unique properties of nanobodies," said Hidde Ploegh, PhD, immunologist at Boston Children's Cellular and Molecular Medicine program and principal investigator at PNAS study.
A useful attribute is their improved targeting capability. Ploegh and his team of Boston Children's, in collaboration with Noo Jalikhani, PhD, and Richard Hynes, PhD of the MIT's Koch Integrative Cancer Research Institute, have used nanobodies to transport medical officers. Imaging, allowing accurate visualization of metastatic cancers.
The Hynes team targeted nanobodies on the extracellular matrix of the tumor, or on ECM imaging agents, which aimed not at the cancer cells themselves, but at the surrounding environment. Such markers are common to many tumors, but do not usually appear on normal cells.
"Our lab and the Hynes lab are among the few organizations that are actively pursuing this targeting approach to the tumor microenvironment," says Ploegh. "Most labs are looking for tumor-specific antigens."
Target tumor protectors
Ploegh's lab has taken this idea for T-cell-based therapy. His team, including members of the Hynes lab, is attacking the very factors that make solid tumors difficult to treat.
The CAR T cells that they created were dotted with nanobodies that recognize specific proteins in the tumor environment, transmitting signals asking them to kill any cell to which they have linked. A protein, EIIIB, a variant of fibronectin, is found only on newly formed blood vessels that provide nutrients to tumors. Another, PD-L1, is an immunosuppressive protein that most cancers use to silence nearby T cells.
Biochemist Jessica Ingram, PhD of the Dana-Farber Cancer Institute, Ploegh's partner and co-author of the paper, led the manufacturing process. She was driving to Amherst, Mbad., To collect the T-cells from two alpacas, Bryson and Sanchez, inject them with the antigen of interest and collect their blood for further processing in Boston to generate mini-antibodies.
Eliminate melanoma and colon cancer
Tested on two distinct murine models of melanoma, as well as on a model of adenocarcinoma of the colon in mice, nanobodies-based CAR T cells killed tumor cells, significantly slowed tumor growth and improved animal survival, without apparent apparent side effects.
Ploegh thinks that artificial T cells act by combining several factors. They have damaged the tumor tissue, which tends to stimulate inflammatory immune responses. Targeting EIIIB can damage blood vessels so as to reduce blood supply to tumors, while making them more permeable to anticancer drugs.
"If you destroy the local blood supply and cause vascular leaks, you could possibly improve the distribution of other objects that might have trouble entering," says Ploegh. "I think we should consider this as part of a combination therapy."
Future Directions
Ploegh thinks that his team's approach could be helpful in many solid tumors. He is particularly interested in nanobody-based T-cell CAR tests in models of pancreatic cancer and cholangiocarcinoma, a cancer of the bile ducts of which Ingram died in 2018.
The technology itself can be pushed even further, says Ploegh.
"Nanobodies could potentially carry a cytokine to boost the immune response to the tumor, toxic molecules that kill the tumor, and radioisotopes to irradiate the tumor at close range," he says. "The CAR T-cells are the ram that would open the door, the other elements would finish the job, in theory, you could equip a single T-cell with multiple chimerical antigen receptors and get even more precision. "
Yushu Joy Xie, a graduate student in the Children's Program in Cellular and Molecular Medicine from Boston for Children and the Koch Institute at MIT, was the first author of the paper. Supporters include the Lustgarten Foundation, the National Science Foundation, the National Institutes of Health, the American Gastroenterological Association, the Howard Hughes Medical Institute's Department of Defense, and the National Cancer Institute. See the document for more details on authors and funders.
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