New Approach Enables CAR T Therapy Target Multiple Proteins On Different Types Of Cells At The Same Time Or One After Another

Researchers at the University of Pittsburgh have made a breakthrough in cancer treatment by creating a universal receptor system that can enable T cells to recognize any cell surface target.

This new technology allows for highly customizable immunotherapies, including CAR T cell therapy, which has produced significant results in certain blood cancers. Published in Nature Communications, the new method involves engineering T cells with receptors that carry a “SNAPtag” that can fuse with antibodies that target different proteins.

By adjusting the type or dosage of these antibodies, the treatment can be personalized for optimal immune responses. The researchers’ SNAP approach has been successfully tested in two important receptors: CAR receptors, which coordinate a suite of immune responses, and SynNotch, a synthetic receptor that can activate almost any gene. With the addition of SNAP, the possibilities for customized cancer therapies become nearly endless.

“We showed for the first time that we can make a universal SynNotch receptor,” remarks senior author Jason Lohmueller.

“This SNAP-SynNotch system is super programmable because you can have both designer input and designer gene output.

“Our hope is that we can use this approach to make cell therapies and deliver genes for cancer, autoimmune disorders, organ transplantation tolerance and more.”

CAR T cell immunotherapy is a cutting-edge treatment that utilizes a patient’s own cells, which are genetically modified to recognize specific proteins on cancer cells. These modified cells are then reintroduced into the patient’s body, where they can identify and target cancer cells with greater accuracy and potency than traditional treatments.

“One of the big problems with CAR T therapy is that you’re targeting just one protein,” adds Lohmueller. “If the tumor evolves to lose that protein or downregulate it, you need to re-engineer the T cells a second time, which is a highly involved and expensive process.”

To address this issue, Lohmueller with first author Elisa Ruffo developed a novel approach that utilizes bio-orthogonal chemistry to engineer T cells with receptors that bear a universal “SNAPtag” enzyme. By administering these cells along with cancer-targeting antibodies labeled with benzylguanine, the SNAPtag fuses the antibody to the receptor, allowing the receptor to recognize various tumor features. This process enables the development of universal SNAP-CAR T cells that can recognize any cell surface target, offering a highly customizable approach for immunotherapies in cancer and other diseases.

“What’s unique about our approach is how the T cell interacts with the antibody. It’s not just binding, but fusing via covalent attachment — the strongest form of chemical bond,” points out Lohmueller. “This type of bio-orthogonal approach has been shown to work in animals for imaging purposes, but we’re among the first to use it therapeutically, so we’re really pushing the boundaries of covalent technology.”

One of the benefits of the strong covalent bond between the SNAPtag enzyme and cancer-targeting antibodies is that the receptor can be activated with lower doses of the antibody, according to Lohmueller. This bio-orthogonal approach also allows for weaker interactions between antibodies and tumor cells, which expands the range of cancer proteins that can be targeted. Meanwhile, the SNAP-SynNotch system utilizes the covalent bond to withstand mechanical pulling forces that expose a part of the protein when the SynNotch receptor is activated. The protein is then cut, releasing a transcription factor that activates the expression of a selected gene, making it a key factor in the creation of the SNAP-SynNotch cells.

“We found that we needed the strength of a covalent bond to tolerate that pulling force,” adds Lohmueller. “If we just had binding between receptor and antibody, the receptor would come apart and we wouldn’t get signaling.”

By including the matching antibodies, the researchers demonstrated that their universal SNAP-CAR and SNAP-SynNotch receptors could be triggered in response to many stimuli. The ability of SNAP-CAR T cells to concurrently target several proteins on various cell types raises the possibility that they may prevent cancer recurrence caused by changes in tumor targets or loss of those targets.

In a rodent model of cancer, treatment with SNAP-CAR T cells shrank tumors and significantly prolonged survival, an important proof-of-concept that paves the way for clinical trials in collaboration with Coeptis Therapeutics, which has licensed Pitt’s SNAP-CAR technology.

Source: 10.1038/s41467-023-37863-5

Image Credit: Getty