Researchers have synthesized small organic molecules called adaptors that have a tumor-specific ligand on one end and FITC on the other. Instead of engineering a different chimeric antigen receptor (CAR) on T cells for each unique tumor antigen, these antigen-specific adaptors can be used to bridge FITC-binding CAR T and tumor cells.
The field of chimeric antigen receptor (CAR) T-cell therapy continues to evolve rapidly, with researchers devising increasingly ingenious ways to improve the ability of these engineered T cells to seek out and eradicate tumors while minimizing side effects.
At Purdue University in West Lafayette, IN, chemist Philip Low, PhD, and doctoral student Yong-Gu Lee have synthesized small organic molecules called adaptors that direct CAR T cells to tumor cells. These molecules are outfitted with the dye FITC on one end, and a ligand with high affinity for a specific tumor antigen on the other. The individual adaptors are then administered alongside T cells engineered to bind FITC.
“Without an adaptor, our CAR T cells can't ‘see’ the targeted antigen,” Low explains. “The adaptor serves as a bridge that forces engagement and subsequent tumor lysis.” Because tumor recognition occurs through the adaptor, “we can use the same FITC-binding CAR T cells to eliminate even highly heterogeneous tumors, when they're administered with the right cocktail of different adaptors,” he adds. “There's no need to engineer a new T cell to discern each unique tumor antigen. Synthesizing small molecules is much easier and less time-consuming.”
These adaptors are also short-lived, Low says, surviving for no more than 60 minutes in vivo, which means treatment can be quickly terminated if life-threatening immune side effects—chiefly cytokine release syndrome—arise. “Once CAR T cells are infused and go to work, they're stimulated to proliferate each time they kill—even after the tumor is fully eradicated,” he observes. “You can't easily call off your dogs, so to speak. With our approach, we can pull the plug on CAR T-cell activity just by discontinuing adaptor administration.”
One of the adaptors produced by Low and Lee contains folate as its tumor-specific ligand, for which “tumor cells have a tremendous appetite—about 40% of human cancers express the folate receptor [FR], but few normal cells do,” Low notes. Another bears DUPA, a ligand that targets the prostate-specific membrane antigen. They've also designed adaptors that bind the neurokinin-1 receptor (NK1R) on neuroendocrine tumors, and carbonic anhydrase IX, which Low says is “overexpressed on any tumor that's even slightly hypoxic.”
In cell lines and mice, Low and Lee have demonstrated that tumor destruction by FITC-binding CAR T cells occurs only when the correct antigen-specific adaptor is added. They've also successfully eradicated two different tumor types in the same mouse by administering the appropriate pair of adaptors—in this instance, targeting FR and NK1R.
Michel Sadelain, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, NY, considers Low and Lee's work “an elegant approach that fits one of the field's emerging themes, namely remote control of CAR T cells by providing some other molecule to trigger or curb activity.” However, he thinks the short half-life of the adaptors, although useful for controlling potential toxicity, could pose a clinical challenge.
“We don't know how long CAR T-cell activity needs to be maintained in individual patients for tumor elimination, but it's probably weeks to months,” Sadelain notes. “So, you'd have to administer the adaptor frequently, or have patients wear a pump for continuous infusion.”
Low acknowledges that “it's early days yet” for his strategy, but he is eager to partner with industry to take it beyond the laboratory. “My objective is to hoist this on the flagpole and see if it flies,” he says. –Alissa Poh
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