Prevent failure of cell transplantation and immunotherapy

Researchers at the University of California, San Francisco (UCSF) have developed a potentially life-saving new approach that may prevent antibodies from triggering immune rejection of genetically engineered therapeutic and transplanted cells. Did.

In contrast to chemical attack initiated by immune cells, antibody-mediated rejection has proven particularly difficult to resolve. Development of these therapies.

A new strategy described in nature biotechnology, using “decoy” receptors to trap antibodies and remove them from circulation before killing therapeutic cells, treating them as foreign invaders. This tactic may also be useful in organ transplantation.

“This antibody-mediated rejection is really difficult to overcome,” said Tobias Deuse, Ph.D., senior author of the study. “So instead of trying to suppress the patient’s immune system, we looked for ways to modify the cells that the patient receives to make it more viable.”

The most popular cell therapy is chimeric antigen receptor (CAR) T cell therapy. These CAR T therapies are often used successfully to treat certain forms of lymphoma, a type of cancer that is deadly. However, deploying them against solid tumors has proven to be much more difficult.

Until recently, most CAR T therapies have been created using the patient’s own cells, but the long-term commercial viability of any type of cell therapy has been limited to ‘allogeneic’ cells (external to the patient’s body). will rely on mass-produced therapeutic cells grown from

Like a transplanted organ, the recipient’s immune system is likely to treat foreign cells and the tissue that develops from them as foreign and reject them, Deuse said.

“We’ve been through this with organ transplants, so we know what happens to cell transplants,” said Deuse. “This problem can be a serious obstacle in all types of allogeneic cell transplantation.”

Clinical trials of allogeneic CAR T therapies have performed worse than treatments derived from patients’ cells, noted Deuse, adding: immunotherapy These free-floating cells come with the added challenge of being more subject to immune attack than cells in transplanted organs.

“We have to find better ways to protect these cells,” he said.

Normally, when an antibody binds to a cell, it acts as a kind of tag, calling immune cells to bind to the antibody and initiate the efficient process of destroying the tagged cell. To stop this chain reaction, Deuse and his team devised a method to trap antibodies before they bind to cells, preventing them from activating the immune response.

The researchers genetically engineered three types of cells—insulin-producing islet cells, thyroid cells, and CAR T cells—so that each type of cell would produce large amounts of a protein called CD64 and display it on its surface. I made it

In these engineered cells, CD64, which binds tightly to the antibodies responsible for this type of immune rejection, acts as a kind of decoy, trapping the antibodies and binding them to the engineered cells, thus activating the immune cells. not converted.

“We found that we could capture these antibodies at high levels, so we were able to protect therapeutic cells very strongly,” explains Deuse. “This is a clear proof of concept for this approach.”

There is still work to be done before testing the approach in cells designed for therapy or transplantation, he said. Such cells are biologically sophisticated, but expensive and difficult to manufacture.

“We hope that our concept will aid in the development of universally usable allogeneic cells,” concluded Deuse. “Then cell therapy treatments will become cheaper and more accessible, and more patients will receive them.”