Novel CAR T Cells Give Cancer A One-Two Punch
By Deborah Borfitz
February 1, 2022 | In an entirely new direction for immunotherapy, researchers at the Sloan Kettering Institute (SKI) have genetically engineered chimeric antigen receptor (CAR) T cells to produce potentially synergistic, small-molecule drugs that can penetrate a solid tumor. The discovery came out of an unrelated antibiotics project in the lab of Derek Tan, Ph.D., chemical biology program chair at SKI.
As Tan tells it, the lab had been creating a variety of enzyme inhibitors over the past two decades and found a highly toxic compound that was sometimes seen as a trace impurity from the synthetic process. It’s a natural product called sulfamoyladenosine (AMS), which turned out to be the perfect candidate for a demonstration of the “micropharmacy” concept.
The notion of trying to create CAR T cells that would double as a drug-making factory for cancer drugs was that of physician-scientist David A. Scheinberg, chair of SKI’s molecular pharmacology program who also directs Memorial Sloan Kettering Cancer Center’s (MSKCC’s) Center for Experimental Therapeutics. “He walked into my office one day and asked if I had any super potent cytotoxic molecules because he had an idea for a ‘targetable micropharmacy’.”
Long term, the collaborators hope to have a CAR T cell that really does synthesis of a small-molecule drug, says Tan. But they began with an experiment where AMS was masked as a nontoxic prodrug that gets released at the tumor site by a CAR T cell engineered to express the enzyme that cleaves off the masking group.
The modular platform is described in a study that recently published in Nature Chemical Biology (DOI: 10.1038/s41589-021-00932-1). In it, the research team show that their so-called “Synthetic Enzyme-Armed KillER” (SEAKER) cells exhibit enhanced anticancer activity with small-molecule prodrugs both in vitro and in vivo in mouse tumor models.
A clinical stage immune-oncology company, CoImmune, has licensed the technology from Memorial Sloan Kettering to develop it for human trials.
It will easily be a few years before clinical trials launch, Tan says. The work ahead includes manufacturing of the small molecule prodrug and engineered cells as well as the usual preclinical assessments required for regulatory authorization to use those investigational products in humans.
One significant finding of the study is that “the antibodies that the mice elicit in response to the bacterial enzymes don’t neutralize the enzyme activity,” says Tan. Important next steps include demonstrating efficacy in immunocompetent mouse models.
The modularity of the SEAKER platform was demonstrated using three classes of small-molecule drugs with different mechanisms of action. But it is expected to be applicable for a wide range of drugs and diseases beyond cancer, Tan says.
Of particular interest to Tan as a synthetic organic chemist is investigating the use of human enzymes that may not have the same immunogenicity as bacterial enzymes, he says. It might also be possible to use enzymes that activate the cytotoxicity or other activity of a small-molecule drug by building onto it rather than simply cleaving off a large masking group.
Tan, Scheinberg, and former MSKCC colleague Renier Brentjens (now chair of medicine at Roswell Park Cancer Center) all have sponsored research agreements with CoImmune. They also hold equity in the company and serve on its scientific advisory board.
They are hopeful that their engineered SEAKER cells “provide a way to overcome some of the existing limitations of CAR T cells… one of the big ones being their application to solid tumors,” says Tan. As just demonstrated, they succeeded in getting cleaving enzymes as well as small-molecule drugs to thoroughly diffuse into tumors—unlike T cells, which are limited in their ability to penetrate a dense mass of tissue.
Other limitations of current CAR T models, which could potentially be overcome with the novel platform, include “escape” of antigen-negative cells in heterogeneous tumors from therapy and the fact that CAR T cells become “exhausted” before they’ve finished the job, he adds. The retooled CAR T cells can deliver a toxic drug payload directly to a tumor to kill both tumor cells that contain the cancer marker as well as cancer cells nearby that do not—and can produce the drug even after they are immunologically dysfunctional.