Researchers engineer a universal receptor system for cell immunotherapies

Chimeric antigen receptor (CAR) T cell therapy is a promising immunotherapy against cancer. The idea is to fortify a person’s immune system to fight its own battle by boosting T cells with the ability to ferret out tumor-associated antigens.

But engineering CAR-T cells is a slow and arduous process, with each batch usually customized to recognize only one antigen. In a new paper, a group of researchers has devised a solution to broaden the versatility of engineered CAR-T cells. They add third-party antibodies that contain a reactive benzylguanine group (Nat. Comm. 2023, DOI: 10.1038/s41467-023-37863-5).

The pairing of a receptor and antigen is often described as a lock-and-key system to illustrate the specificity of their interactions. For several years, the CAR-T community has worked to increase the universality of the “locks”—the receptors that decorate the surface of CAR-T cells—so that they can interact with multiple tumor-antigen “keys.”

In the team’s therapeutic strategy, it is the antibodies rather than the CAR-T cells that take the spotlight. These chemically modified antibodies serve as universal adapters between the CAR-T cell and various tumor antigens.

“An antibody is not easy to chemically modify, but much easier to chemically modify than an entire cell,” Alexander Deiters, a University of Pittsburgh chemist and one of the study’s authors, says.

The researchers engineered CAR-T cells with receptors that carrya SNAPtag, a modified human O-6-methylguanine-DNA methyltransferase that is commonly used to label proteins. This SNAPtag covalently binds with benzylguanine.

By attaching benzylguanine onto various off-the-shelf antibodies, the researchers allow for a single CAR-T cell to recognize multiple tumor targets via the antibodies themselves. The team demonstrated that their SNAP-CAR cell platform was able to shrink tumors in mice and prolong their survival.

The same universal, antibody-mediated receptor system was also able to revamp synthetic Notch receptors. These membrane proteins can kickstart the expression of target genes and therefore the production of immune signaling molecules. The engineered SNAP-Notch receptors stir awake when benzylguanine-toting antibodies chemically fuse to them.

The covalent bond between the SNAP-tag and the benzylguanine is key to the receptor-antibody therapeutic performance. The researchers’ modeling studies predicted that the strong covalent interactions could bring about a more potent CAR-T therapeutic effect with a lower dose, reducing the treatment’s potential toxicity. In the synthetic Notch experiments, nothing short of a covalent tie between receptor and antibody intermediate was strong enough to trigger a response.

Moreover, the antibody platform provides new opportunities to modulate the therapeutic response of the CAR-T system. One way is to tune the antibody dose. The benzylguanine-based antibody-adapter system also presents a kill switch—the study showed that swamping any prowling CAR-T cells with loose benzylguanine molecules could thwart the cancer killers from reaching the antibodies, thus interrupting the link between the CAR-T cells and their targets. “It could be a way to just turn off the receptors without eliminating the CAR-T cells,” says Jason Lohmueller, an immunologist at the University of Pittsburgh and the study’s corresponding author.

“It’s a great paper,” says Paulina Velasquez, a physician-scientist at St. Jude Children’s Research Hospital. “Having this adapter technology in the CAR setting gives you a lot of flexibility.” Her main concern is the treatment’s scalability, an issue that’s common to any investigative treatment. “Getting it to the clinic will take some work,” she says.

Lohmueller’s team has licensed the SNAPtag-benzylguanine technology to the CAR-T firm Coeptis Therapeutics.

Ultimately, the researchers’ goal isn’t to engineer a more effective tumor-slaying CAR-T therapy, but a safer one. Toward this end, the antibody adapters’ tunability makes room for extra selectivity-control measures such as tacking on additional molecular switches that only turn the antibodies on in the presence of chemical stimuli from a tumor microenvironment, Lohmueller says. The SNAPtag-benzylguanine modifier is just the beginning.