Project Grant R43AI179375

ALLOGENEIC BAFF LIGAND BASED CAR T-CELLS AS A NOVEL THERAPY FOR SYSTEMIC LUPUS ERYTHEMATOUS - ABSTRACT SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A COMPLEX, CHRONIC AUTOIMMUNE DISEASE WITH NO CURE WHICH AFFECTS 1.5 MILLION AMERICANS. SLE IS A RHEUMATIC DISEASE WHICH CAN LEAD TO SEVERE ORGAN DYSFUNCTION, INCLUDING END STAGE RENAL DISEASE. AUTOREACTIVE B CELLS HAVE EMERGED AS PRIMARY DRIVERS OF THE DISEASE AND THE PRESENCE OF ANTI-NUCLEAR ANTIBODIES IS A BIOMARKER FOR DIAGNOSIS. THERAPIES TARGETING B CELLS AND THE B CELL ACTIVATING FACTOR (BAFF) SIGNALING AXIS, INCLUDING BELIMUMAB, A MONOCLONAL ANTIBODY TARGETING BAFF, HAVE SHOWN PROMISING RESULTS IN REDUCING SEVERITY OF DISEASE IN B CELL ASSOCIATED AUTOIMMUNITY, BUT THESE TREATMENTS ARE NOT CURATIVE. A RECENT STUDYING USING CD19 CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL THERAPY LED TO B CELL CLEARANCE AND DISEASE REMISSION IN 4 OF 5 PATIENTS. EACH OF THESE PATIENTS WERE IN EARLY-STAGE LUPUS, BUT THE ONE WHO DID NOT RESPOND HAD THE LONGEST-TERM DISEASE AT 9 YEARS. THIS STUDY INDICATES B CELL CLEARANCE CAN RESOLVE SLE DISEASE PROGRESSION, BUT THE CD19-CAR TREATMENT WAS LIMITED IN TARGETING ALL THE AUTOREACTIVE B CELLS, INCLUDING LONG-LIVED PLASMA CELLS WHICH PRODUCE AUTOREACTIVE ANTIBODY BUT DO NOT EXPRESS CD19. WE THUS SEEK TO CIRCUMVENT THIS ISSUE IN A NEW TREATMENT FOR SLE USING AN ALLOGENEIC BAFF-LIGAND BASED CAR D T CELL PRODUCT. THE BAFF FAMILY RECEPTORS BAFFR, TACI, AND BCMA ARE HIGHLY EXPRESSED ON B CELLS AT DIFFERENT PROPORTIONS DEPENDING ON THEIR MATURATION STATE INCLUDING PLASMA CELLS. WE HYPOTHESIZE THAT ELIMINATION OF ALL AUTOREACTIVE B CELLS, INCLUDING LONG-LIVED PLASMA CELLS IN THE BONE MARROW, WILL REDUCE THE PRODUCTION OF AUTOANTIBODIES AND LEAD TO LONG TERM REMISSION. THE USE OF D T CELLS ALLOWS FOR THE MASS PRODUCTION OF ALLOGENEIC CAR T CELLS FROM A SINGLE T CELL DONOR, REDUCING COST AND INCREASING SAFETY OVERSIGHT DURING MANUFACTURING. WE HAVE PRODUCED PRELIMINARY DATA THAT CONFIRMS OUR ABILITY TO USE THE NON-VIRAL TCBUSTER DNA TRANSPOSON SYSTEM TO GENERATE D T CELLS WITH BAFF-CAR EXPRESSION AND SHOW THAT THESE CELLS ARE EFFECTIVE AT ELIMINATING CELLS EXPRESSING THE BAFF FAMILY OF RECEPTORS. TO TEST THE EFFICACY OF THE CAR IN THE CONTEXT OF SLE, WE PROPOSE TWO COMPLEMENTARY AIMS THAT WILL ASSESS THE EXPRESSION OF BAFF RECEPTORS IN SLE PATIENT B CELLS AND TEST THE ACTIVITY AND SELECTIVITY OF THESE CELLS AGAINST PATIENT B CELLS IN VITRO. FINALLY, WE WILL TEST THE EFFICACY OF THE BAFF-CAR D T CELLS IN REDUCING INFLAMMATION, RENAL DISEASE, AND AUTOANTIBODY PRODUCTION IN A HUMANIZED MOUSE MODEL OF SLE. WE HOPE TO IMPROVE OUTCOMES IN SLE BY ADVANCING THIS TECHNOLOGY TO IND-ENABLING STUDIES.