Examining the impact of endogenous CD28 signaling on CAR T cells

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Project Abstract/Summary. Recent advances in immune cell engineering have revolutionized the treatment of blood cancers. Genetic modification of T cells, whose physiological job is to kill infected and mutant cells throughout our bodies, with Chimeric Antigen Receptors (CARs) can redirect T cell killing activity against malignant cells that express certain target proteins on their surface. CARs are built to mimic physiological T cell signaling, which is unique in its requirement for two signals provided by the T cell receptor (TCR) and co-receptors, such as CD28, to induce T cell function. Recent clinical studies in multiple myeloma (MM), a common incurable blood cancer, have shown that CAR T cells are remarkably effective at treating patients who do not respond to standard of care chemotherapies. Despite this, most MM patients relapsed within a year of CAR T cell therapy and the cause of their relapses was not readily apparent. The long-term goal of the project proposed in this grant application is to use our knowledge or T cell signaling to make CAR T cell therapy for MM more effective. To this end, we have found that endogenous CD28 on CAR T cells disrupts their ability to kill MM cells that express CD28 stimulatory proteins CD80 and CD86. However, the same endogenous CD28 is essential for making CAR T cells and we have also found that the CD28 signal provided during the CAR T cell manufacturing process helps determine how good of tumor killers CAR T cells become. Proposed studies seek to 1) identify ways to manipulate CD28 signaling during CAR T cell manufacture that can improve their long-term ability to kill MM cells in patients, and 2) determine how endogenous CD28 signaling causes dysfunction of CAR T cells. Results of these studies will have direct clinical implications because adjustments to the CAR T cell manufacturing process could be rapidly implemented and a drug that blocks CD28 activation, abatacept, is already used to treat people suffering from rheumatoid arthritis.