T cells that attack tumor cells
MAURIZIO DE ANGELIS / Science source
By Jocelyn Kaiser
Researchers have shown in mice that antibodies from designers can inhibit the growth of tumors by targeting two of the most notorious offenders of cancer – the proteins RAS and p53, which are mutated in many tumors but have largely defied drug development efforts. If their promise is met in clinical trials, such drugs could make it possible to release the body’s immune system for difficult-to-treat cancers, including pancreas and ovaries.
“It’s exciting,” said immunologist Jon Weidanz of the University of Texas at Arlington, who co-founded a company working on similar immunotherapies called bispecific antibodies. The new drugs can protrude on a few fragments of p53 or RAS from the surface of a tumor cell – and then cause immune cells to attack it. ‘The therapies have the potential to work if there is a very low target on cells. This is a big deal, ‘says Weidanz, who wrote a comment to the papers.
P53 is a tumor suppressor, and the intact protein helps healthy cells to repair DNA – or self-destruction if the damage cannot be repaired. If p53 is turned off in tumors, it can grow unnoticed. But it is more difficult to target p53 with drugs, because it is much more difficult to restore its activity than to inhibit its activity or shut down its production – more typical drug strategies against the misconduct of proteins.
RAS, which indicates that cells must grow uncontrollably when mutated, was difficult to inhibit with inhibitors due to the smooth shape and lack of clear binding sites.
And both proteins function in cells, making it difficult to fight with manufactured antibodies, versions of the Y-shaped proteins that our immune system uses to mark foreign invaders for destruction. Antibodies cannot enter the cells easily, and therefore drugs based on them may be best against cancer proteins protruding from the surface of a tumor cell.
But although RAS and p53 remain in tumor cells, the surface of the cell carries traces of it, fragments that can be detected by the immune system. To target the fragments of mutants p53 and RAS, known as neoantigens, cancer geneticist Bert Vogelstein’s laboratory at Johns Hopkins University turned to bispecific antibodies. Standard antibodies have two identical arms, but bispecifics are made to have one arm that binds to immune cells called T cells, and another that binds to a cancer cell surface protein, which bridges the cells and activates the immune cell around its to attack new, cancerous mate. .
The challenge was that the pieces of mutant p53 and RAS that can target an antibody are extremely rare on tumor cells – less than ten specimens per cell, the researchers found. The discovery of a bispecific antibody that would bind to them but not to healthy cells took Emkins Hsiue and Jacqueline Douglass and their team from Hopkins more than 5 years. First, they tested a library of antibody fragments to find those that adhere to the p53 and RAS neoantigens. They then transformed these fragments into different bispecific antibody designs and tested what was best for attracting T cells to kill cancer cells in a dish. The strategy was ‘informed trial and error’, says molecular biologist Shibin Zhou of Hopkins, who led the work.
Finally, the team has a p53-directed “diabetic body”, a compact, two-armed antibody, without the stem of a typical Y-shaped antibody. In mice with tumor cells carrying a specific mutation in the p53 gene, this bispecific tumor growth dramatically limited, the researchers reported today in Science. Two separate RAS diabodies have worked well on lines of cultured cells with two different cancer-promoting mutations and have modestly slowed the growth of tumors in mice, the team wrote today Scientific immunology. In a third study led by research fellow Suman Paul, the same type of inhibited double-target antibody also worked in mice against a type of leukemia involving T cells. Science Translational Medicine. The goal was another type of cancer that is difficult to get drugs.
The studies have reservations. To treat patients, researchers must develop a panel of bispecific antibodies adapted to a person’s immune proteins and the specific p53 or RAS genetic mutations in their tumor. (The bispecific leukemia will also need to be linked to a patient’s T-cell cancer.) Because the Y-strain of normal antibodies is missing, the diabetic bodies disappear more quickly from the bloodstream, so they must be administered continuously for weeks. pump worn. by the patient. “There are quite a few ways to do this,” says Vogelstein, who describes the work today during the online conference Advances in Genome Biology and Technology.
Yet outside researchers are enthusiastic. Although other groups are also working on bispecific antibodies that target intracellular cancer proteins, ‘it appears to be one of the first drugs to target mutant P53, a critical tumor suppressor’, says scientist David Scheinberg of the Memorial Sloan Kettering Cancer Center , which consults biotechnology companies operating in this environment. (Hopkins filed patent applications related to the treatments.)
And although researchers are making progress in developing other drugs for RAS cancer, the drugs do not use the immune system and are likely to stop working within 1 year as tumors become resistant, Weidanz predicts. Bispecific antibodies, which can elicit a broad immune response, offer “the potential for a greater war that can hopefully win the immune system.”