Universal Receptor System Developed to Enhance CAR T Cell Immunotherapy

University of Pittsburgh researchers have developed a universal receptor system that enables T cells to recognize any cell surface target. T cells modified to express receptors bearing a universal "SNAPtag" could be combined with different antibodies to create customized CAR T cell and other immunotherapies for optimal immune responses. This approach, described in a paper published in Nature Communications, could give more patients access to the encouraging results CAR T cell therapy has produced in certain blood cancers.

The researchers’ universal SNAPtag approach works in two crucial receptors: CAR receptors, which coordinate a suite 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 customized therapies become almost endless.

CAR T cell therapy involves engineering a patient’s T cells so that they recognize a specific protein on cancer cells before reinfusing them into the patient. One major issue with this therapy is that it targets only one protein, so if the tumor evolves to lose or downregulate that protein, the T cells must be re-engineered, which is an expensive and highly involved process.

To address this issue, the researchers developed universal SNAP-CAR T cells by adding a SNAPtag enzyme to the CAR receptor. Cancer-targeting antibodies, labeled with a molecule called benzylguanine, are administered along with these cells. Via a bio-orthogonal chemistry, the SNAPtag reacts with benzylguanine, fusing the antibody to the receptor. By adding different antibodies, at the same time or one after another, the receptor can recognize different tumor features.

The tight bond formed between the T cell and antibody allows activation of the receptor to be achieved with lower doses of antibody. Using mathematical modeling, the researchers showed that it may also be possible to get activity from weaker interactions between antibodies and tumor cells, offering greater flexibility to the types of cancer proteins that can be targeted. In addition, in a mouse model of cancer, treatment with SNAP-CAR T cells shrank tumors and prolonged survival, demonstrating the potential of this approach for clinical trials.