Chimeric antigen receptor (CAR)-T cells have broadened treatment options for some cancers—particularly certain types of blood cancers. But they have limitations: 1) variable antigen expression patterns on cancer cells can lead to “escape” from the therapy, 2) CAR-T cells can become “exhausted” and even inhibited by the cancer cells themselves, and 3) immunosuppressive tumor microenvironments lead to lack of efficacy against dense solid tumors.
Now, scientists have developed a new type of CAR-T cells that act as a “micropharmacy.” The cells co-express bacterial enzymes that activate prodrugs at the disease site, killing both tumor cells that contain the cancer marker as well as nearby cancer cells that do not. What’s more, the engineered cells can produce the drug even after they become exhausted, and the drug is not suppressed by the cancer.
This work is published in Nature Chemical Biology in the paper, “Engineering CAR-T cells to activate small-molecule drugs in situ.”
“We call them SEAKER cells,” said David Scheinberg, MD, PhD, chair of the molecular pharmacology program at Memorial Sloan Kettering Cancer Center’s Sloan Kettering Institute (SKI). “SEAKER stands for Synthetic Enzyme-Armed KillER cells. These cells combine the target-seeking power of immune cells with the ability to locally generate a potent anticancer drug for double effect.”
The idea of using CAR-T cells to deliver additional therapeutic agents isn’t new. Several research groups have shown it’s possible to get the cells to make immune proteins like antibodies and cytokines. But getting CAR-T cells to produce a small-molecule cancer drug is more challenging.
The molecule used in the study, called AMS, is too powerful to be injected directly into an animal’s bloodstream. But when it is produced locally at the site of a tumor, it is effective at safely killing cancer cells in mice. The scientists have not yet tested the technology in people.
The team linked the cancer drug to another chemical that “masks” its function. Then, they genetically engineered the T cells to make an enzyme that cuts the masking molecule from the drug. When the prodrug is injected into the bloodstream, it circulates through the body. The enzyme produced by the CAR-T cells releases the active part of the prodrug at the site of the tumor.
The scientists tested their SEAKER cells on both cancer cells in culture and in mouse models. In both cases, the SEAKER cells performed better than regular CAR-T cells at killing the cancer cells.
“It’s one of the wildest ideas I’ve ever worked on,” said Derek Tan, PhD, chair of the chemical biology program at the SKI. “It’s very exciting that we got it to work.”
The technology has been licensed by the company CoImmune to develop the CAR-T cell technology for human trials. “There is an opportunity to better understand the limitations of CAR-T cells and specifically engineer new treatment options that have the potential to address challenges with eliminating tumor masses and toxicity,” said Charles Nicolette, PhD, CEO of CoImmune.
“The collaboration with CoImmune is exciting because we need a company to take this on to scale up and manufacture a standardized product,” Scheinberg added.
Another part of the appeal of the SEAKER technology is that it has more than one possible application. “You could imagine it being used to produce drugs to fight other conditions, such as autoimmune diseases and infections,” Scheinberg said. But for now, the focus of the MSK researchers and CoImmune will be on cancer. Scheinberg speculates that a clinical trial in cancer is about two to three years away.