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Researchers at the University of Pittsburgh have developed a universal receptor system that allows T cells to recognize any target on the cell surface, enabling highly adaptive CAR T cells and other immunotherapies to treat cancer and other diseases. The discovery could extend to solid tumors and give more patients access to the game-changing results that CAR T cell therapy has brought to certain blood cancers.
Described in a Nature Communications study published today, May 9, the new approach involves engineering T cells with receptors carrying a universal “SNAPtag” that is fused to antibodies targeting different proteins. By changing the type or dose of these antibodies, treatments can be tailored for an optimal immune response.
The researchers showed that their SNAP approach works in two important receptors: CAR receptors, a synthetic T-cell receptor that coordinates an array of immune responses, and SynNotch, a synthetic receptor that can be programmed to activate almost any gene. With the addition of SNAP, the possibilities for personalized therapies become almost endless.
“We have shown for the first time that we can make a universal SynNotch receptor. This SNAP-SynNotch system is super programmable because you can have both designer input and designer gene output,” said senior author Jason Loehmuller, Ph.D., assistant professor of surgery and immunology in the Department of Surgical Oncology at Pitt School of Medicine and researcher at the UPMC Hillman Cancer Center. “Our hope is that we can use this approach to make cell therapies and deliver genes for cancer, autoimmune diseases, organ transplant tolerance, and much more.”
CAR T cell immunotherapy involves engineering the patient’s own cells so that the T cell receptor recognizes a specific protein on the cancer cells before infusing them back into the patient.
“One of the big problems with CAR T therapy is that you only target one protein,” Lohmuller explained. “If the tumor evolves to lose this protein or downregulate it, you have to reconstitute the T cells a second time, which is a very involved and expensive process.”
To overcome this problem, Lohmueller, first author Elisa Ruffo, Ph.D., postdoctoral fellow at Pitt, Alexander Deiters, Ph.D., professor of chemistry at Pitt, and their colleagues developed universal SNAP-CAR T cells by adding a SNAPtag enzyme to the CAR receptor. These cells are administered along with cancer-targeting antibodies that are labeled with a molecule called benzylguanine.
Through bio-orthogonal chemistry—a type of reaction that occurs in living systems without interfering with natural processes—SNAPtag reacts with benzylguanine, fusing the antibody to the receptor. Adding different antibodies, at the same time or one after the other, allows the receptor to recognize different characteristics of the tumor.
“What is unique about our approach is how the T cell interacts with the antibody. It’s not just binding, but fusion through covalent attachment—the strongest form of chemical bonding,” Lohmuller explained. “This type of bioorthogonal 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.”
An advantage of this close association means that receptor activation can be achieved with lower doses of antibody, Lohmuller said. Using mathematical modeling, graduate student Adam Bucci and Natasha Miskov-Zhivanov, PhD, assistant professor of electrical and computer engineering in the Pete Swanson School of Engineering, showed that it may also be possible to derive activity from weaker interactions between antibodies and tumor cells , giving greater flexibility in the types of cancer proteins that can be targeted.
The covalent bond was also the secret ingredient in creating SNAP-SynNotch cells. When a SynNotch receptor is activated, mechanical pulling forces stretch the receptor to expose a portion of the protein, which is then cleaved to release a transcription factor that travels to the cell’s nucleus to turn on the expression of a selected gene.
“We found that we need the strength of a covalent bond to carry this attractive force,” Lohmuller explained. “If we just had binding between the receptor and the antibody, the receptor would break down and we wouldn’t get a signal.”
The researchers showed that their universal SNAP-CAR and SNAP-SynNotch receptors can be activated in response to different targets by adding the corresponding antibodies. SNAP-CAR T cells are also able to simultaneously target multiple proteins to different cell types, suggesting that they may help avoid cancer recurrence due to variations in tumor targets or loss of those targets.
In a mouse model of cancer, treatment with SNAP-CAR T cells shrinks tumors and significantly prolongs survival, an important proof-of-concept that sets the stage for testing this approach in clinical trials in partnership with Coeptis Therapeutics, which has licensed SNAP-CAR technology from Pitt .
Elisa Ruffo et al, Post-translational covalent assembly of CAR and synNotch receptors for programmable antigen targeting, Nature Communications (2023). DOI: 10.1038/s41467-023-37863-5. www.nature.com/articles/s41467-023-37863-5