Altering cells could ease a promising
cancer therapy’s side effects
Scientists frustrated by the nasty side effects of a promising immune therapy that effectively kills cancer cells have found a way to keep the therapy working longer while eliminating the devastating reactions.
If the new technique is proven to be as successful in humans as it was in mice, scientists want to incorporate it into the therapy, called adoptive cell transfer.
The therapy takes advantage of a patient’s natural immune system by using a patient’s own blood; purifying it; and extracting immune cells, called killer T cells, which are designed to destroy foreign intruder cells. Scientists then genetically alter those cells — to make them especially adept at finding and destroying specific cancer cells — and inject them back into the patient’s circulatory system.
To succeed, T cells need nudges from a protein called interleukin-2, which binds to receptors on the surface of T cells. When faced with such biological threats as bacteria or viruses, our bodies secrete the IL-2 protein, whose job is to activate T cells.
“These bioengineered T cells need IL-2 to survive, to work and to expand in number, just as our natural ones do,” said Christopher Garcia, PhD, professor of molecular and cellular physiology and of structural biology, and senior author of a study about the technique published March 2 in Science.
But nature doesn’t produce enough IL-2 to keep altered T cells revved up, so they fade and burn out, Garcia said. To keep modified T cells active, patients must be injected with IL-2 “booster shots.” Huge doses of the powerful protein, however, have nasty side effects that can outweigh treatment benefits. They include weight loss, restricted mobility, hypothermia, and enlarged spleen and lymph glands. It also can cause inflammation in cells that are better left alone during cancer treatment. Some patients also experience pulmonary edema, in which their lung tissue fills up with fluid, making it difficult or impossible for them to breathe.
Garcia and his team created a workaround by engineering new versions of both IL-2 and its corresponding receptor that bind only to each other. This keeps cancer-targeting T cells working without causing side effects by activating other T cells, he said.
Garcia credited Jonathan Sockolosky, PhD, lead author of the study and former postdoctoral scholar, with pairing up the modified protein and receptor. In the lab, Garcia’s group snapped modified receptors onto T cells from mice and showed that these T cells responded to modified IL-2 exactly as natural T cells would be expected to respond to ordinary IL-2. Then, in tests in mice, collaborators from UCLA and UCSF shrank tumors using bioengineered T cells that had been outfitted with modified proteins and receptors, with none of the side effects that come from natural IL-2 infusions.
“Adoptive cell therapy is on the cusp of becoming a revolutionary new approach to cancer treatment,” Garcia said. “It’s undergoing explosive growth — it’s a multibillion-dollar biotechnology industry already, and it’s going to become as routine as bone marrow transplants are now. But all of the approaches in development today need IL-2, so new and better ways of delivering IL-2 are a critical unmet need.”