Project Grant R43AI179244

IN VIVO GENE DELIVERY TO REGULATORY T CELLS TO DRASTICALLY REDUCE THE COST OF REGULATORY T CELL THERAPY - PROJECT SUMMARY PROJECT TITLE: IN VIVO GENE DELIVERY TO REGULATORY T CELLS TO DRASTICALLY REDUCE THE COST OF REGULATORY T CELL THERAPY ORGANIZATION: GIGAMUNE INC. PI: DAVID JOHNSON, PH.D. OVER 9,000 PATIENTS WILL RECEIVE LIVER TRANSPLANTS THIS YEAR, AND ABOUT 75% OF THOSE PATIENTS WILL SURVIVE AT LEAST 5 YEARS. LONG TERM IMMUNE SUPPRESSION IS REQUIRED FOR NEARLY ALL PATIENTS, BUT MOST IMMUNE SUPPRESSANTS (E.G., CORTICOSTEROIDS) ARE SYSTEMIC RATHER THAN TARGETED. IMMUNE SUPPRESSANTS LEAD TO LONG-TERM TOXICITIES SUCH AS MALIGNANCY (5% INCIDENCE), LYMPHOPROLIFERATIVE DISORDER (3% INCIDENCE), AND INFECTIONS. ABOUT 50% OF PATIENTS NEVER TOLERATE THE TRANSPLANT TO THE POINT WHERE IMMUNE SUPPRESSANTS CAN BE REMOVED. ADOPTIVE CELL THERAPIES WHEREIN CHIMERIC ANTIGEN RECEPTORS (CARS) OR T CELL RECEPTORS (TCRS) ARE ENGINEERED INTO AUTOLOGOUS T CELLS EX VIVO HAVE SHOWN STRONG CLINICAL EFFICACY AND SAFETY. REGULATORY T CELLS ENGINEERED WITH CARS ("CAR TREGS") ARE A RELATIVELY NEW CONCEPT WHEREIN CARS ARE USED TO DIRECT ANTIGEN-SPECIFIC IMMUNE SUPPRESSION. CAR-TREGS ARE UNDER PRECLINICAL AND CLINICAL INVESTIGATION FOR INDICATIONS SUCH AS TRANSPLANT AND AUTOIMMUNITY, WITH THE GOAL OF INDUCING LONG-TERM TOLERANCE WITHOUT TOXICITIES. HOWEVER, THE COST OF MANUFACTURING CELL THERAPIES IS HUNDREDS OF THOUSANDS OF DOLLARS PER PATIENT, DRIVING TOTAL PER-PATIENT COSTS TO UP TO $1 MILLION PER PATIENT. RECENT PIONEERING WORK USED LIPID NANOPARTICLES (LNPS) AND LENTIVIRUS (LVS) TO DELIVER CARS TO T CELLS IN VIVO, ELIMINATING THE NEED FOR MANUFACTURE OF ENGINEERED CELLS EX VIVO. GIGAMUNE HAS DEVELOPED A NOVEL NEXT- GENERATION LENTIVIRUS PLATFORM (GIGALENTITM) FOR IN VIVO DELIVERY OF CARS AND TCRS SPECIFICALLY TO T CELLS IN VIVO. THE SPECIFIC AIM OF THIS PHASE I SBIR PROJECT IS TO USE IN VITRO MODELS TO ASSESS THE TRANSLATIONAL POTENTIAL OF CHIMERIC ANTIGEN RECEPTOR GENE DELIVERY TO REGULATORY T CELLS FOR LIVER TRANSPLANT TOLERANCE, AT DRASTICALLY REDUCED COST COMPARED TO CONVENTIONAL CELL THERAPY.