CAR T cells modified to produce bacterial enzymes can activate tumor-killing prodrugs. The cells, dubbed SEAKER cells, home in on tumor cells, proliferate, and produce large quantities of the enzymes, which then activate the prodrug. The research demonstrates that CAR T cells' cancer-killing ability can be boosted in vitro and increase survival of mice with tumors.
Researchers have demonstrated a novel approach to boost the effectiveness of chimeric antigen receptor (CAR) T cells—using them to activate chemotherapies (Nat Chem Biol 2022;18:216–25). The method proved successful against tumors in mice, and after further development, a company wants to test it in clinical trials.
CAR T cells can work well against B-cell cancers, but researchers looking to increase the cells’ potency or to treat solid tumors have run into some obstacles. For example, tumor cells can develop resistance by shedding their target protein, usually CD19. And CAR T cells can stop attacking when they enter tumors and encounter the immunosuppressive environment.
A team led by David Scheinberg, MD, PhD, and Derek Tan, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, upgraded CAR T cells by exploiting their homing ability. They engineered the cells to produce carboxypeptidase G2 (CPG2) or β-lactamase (β-Lac), bacterial enzymes that can activate tumor-killing prodrugs. They dubbed these modified cells SEAKER cells.
Patients would receive SEAKER cell infusions and then a prodrug to treat their cancer. The cells, which continually make and release the enzymes, proliferate rapidly when they encounter CD19-expressing tumor cells. This, in turn, causes a burst of enzyme production, boosting the concentration of active drug.
In vitro experiments revealed that the SEAKER cell–prodrug combination increases the killing ability of these cells. However, the researchers found that the prodrugs did not boost the potency of standard CAR T cells.
To evaluate the SEAKER cells’ effectiveness against tumors, the scientists implanted mice with Burkitt lymphoma cells, which carry CD19. The animals were then divided into multiple groups that received no treatment, SEAKER cells that produced CPG2 or β-Lac, or CPG2- or β-Lac–producing SEAKER cells and a prodrug. The untreated mice and those that received only SEAKER cells survived for less than 30 days. However, mice dosed with CPG2-making SEAKER cells and a prodrug lived about 50% longer; the survival benefit was even greater for mice infused with β-Lac–generating SEAKER cells and a prodrug. However, Scheinberg says it's too early to judge which enzyme will be most useful.
The team also tested SEAKER cells in mice with tumors that contained CD19-positive and CD19-negative leukemia cells. The SEAKER cells killed leukemia cells regardless of CD19 expression. “That's a potential advantage,” says Scheinberg, because SEAKER cells can destroy cancer cells that have lost target antigens. In addition, SEAKER cells provide greater control over where and when drugs are active, he says.
Scheinberg and Tan are co-inventors of the SEAKER technology and consultants for CoImmune, which is working to commercialize it. Trials are a few years away, says Scheinberg, but the approach “could avoid a lot of the hurdles that have prevented CAR T cells from working very well with solid tumors.”
“I think it has significant potential,” says Philip Low, PhD, of Purdue University in West Lafayette, IN, who wasn't connected to the study. However, Low notes that researchers still have questions to answer, such as how to protect SEAKER cells from destruction by the recipient's immune system. “It may have a way to go before it's going to be a stable therapy that's effective in a broad spectrum of patients.” –Mitch Leslie