Project Grant F31CA310302

IMPROVING EFFICACY OF TSHR-CART BY TARGETING SUPPRESSIVE MYELOID CELLS - PROJECT SUMMARY/ABSTRACT THE INCIDENCE OF THYROID CANCER IS RISING ACROSS THE UNITED STATES, WITH PROJECTIONS SHOWING IT WILL BECOME THE FOURTH MOST COMMON TYPE OF CANCER IN THE WORLD IN THE NEAR FUTURE. WHILE MANY PATIENTS ARE TREATED SUCCESSFULLY, AGGRESSIVE, DEDIFFERENTIATED, AND METASTATIC THYROID CANCERS HAVE A POOR PROGNOSIS AND LIMITED TREATMENT OPTIONS. CHIMERIC ANTIGEN RECEPTOR T (CART) CELLS ARE T CELLS ENGINEERED TO EXPRESS AN ARTIFICIAL RECEPTOR TARGETING A SPECIFIC SURFACE MARKER, LEADING THE CELLS TO ATTACK MALIGNANT TISSUE. CART CELL THERAPY HAS SHOWN UNPRECEDENTED SUCCESS IN THE TREATMENT OF HEMATOLOGICAL MALIGNANCIES. HOWEVER, EFFICACY OF CART CELLS IN SOLID TUMORS REMAINS MODEST. THYROID-STIMULATING HORMONE RECEPTOR (TSHR) IS AN APPEALING TARGET FOR CART CELL THERAPY AS ITS EXPRESSION IS LARGELY LIMITED TO THE THYROID GLAND. DUE TO THIS LIMITED EXPRESSION, OUR GROUP DESIGNED AND GENERATED TSHR-CART CELLS AND DEMONSTRATED ANTIGEN-SPECIFIC ACTIVATION AND ANTI-TUMOR EFFICACY IN PRECLINICAL MODELS. HOWEVER, THE TUMOR MICROENVIRONMENT (TME) IS A MAJOR LIMITING FACTOR TO CART SUCCESS IN SOLID TUMORS. OUR PRELIMINARY DATA IDENTIFIED SUPPRESSIVE MYELOID CELLS INCLUDING TUMOR ASSOCIATED MACROPHAGES AND MYELOID DERIVED SUPPRESSOR CELLS AS THE MAJOR CELL TYPES SUPPRESSING TSHR-CART CELLS IN PRECLINICAL MOUSE MODELS. SUPPRESSIVE MYELOID CELLS EXPRESS HIGH LEVELS OF COLONY STIMULATING FACTOR 1 RECEPTOR (CSF1R), AND WE DEMONSTRATED THAT CSF1R TARGETING LED TO IMPROVED TSHR CART CELL THERAPY IN PRECLINICAL MODELS. THESE PRELIMINARY DATA LED TO OUR CENTRAL HYPOTHESIS THAT SUPPRESSIVE MYELOID CELL-MEDIATED INHIBITION OF CART CELLS CAN BE SAFELY AMELIORATED THROUGH CSF1R TARGETING WITHIN THE TME. THE OVERALL GOAL OF THIS PROJECT IS TO BETTER UNDERSTAND MYELOID CELL-MEDIATED CART SUPPRESSION AND DEVELOP STRATEGIES TO SAFELY AND EFFECTIVELY TARGET CSF1R ON SUPPRESSIVE MYELOID CELLS WITHIN THE TME OF THYROID CANCER. TO TEST THIS HYPOTHESIS, WE HAVE DESIGNED TWO SPECIFIC AIMS. AIM 1 WILL STUDY THE ROLE OF CSF1R IN SUPPRESSIVE MYELOID CELL-MEDIATED TSHR- CART INHIBITION. WE WILL EMPLOY MULTIPLE STRATEGIES TO ALTER CSF1R EXPRESSION INCLUDING SILENCING RNA, MESSENGER RNA, AND CSF1R KNOCKOUT MICE TO DEFINE THE IMPACTS ON TSHR-CART SUPPRESSION. AIM 2 WILL ASSESS THE EFFICACY OF A NOVEL TSHR-CART CELL THERAPY WHICH SIMULTANEOUSLY TARGETS BOTH THYROID CANCER CELLS AND SUPPRESSIVE MYELOID CELLS IN THE TME. OVERALL, THESE FINDINGS WILL DEFINE THE ROLE OF CSF1R IN SUPPRESSIVE MYELOID CELL INHIBITION OF CART CELLS AND HIGHLIGHT A NOVEL AND CLINICALLY TRANSLATABLE STRATEGY TO TARGET SUPPRESSIVE MYELOID CELLS WITH CART CELL THERAPY. AT THE COMPLETION OF THIS WORK, I WILL ACQUIRE SKILLS IN SYNTHETIC BIOLOGY, AND VECTOR DESIGN, SINGLE CELL TRANSCRIPTOMICS, AND TRANSLATIONAL SCIENCE WHILE CONTINUING TO IMPROVE MY SKILLS IN MOUSE MODELING. AS SUPPRESSIVE MYELOID CELLS ARE ABUNDANT IN MANY SOLID TUMORS, THIS WORK WILL HAVE BROAD IMPLICATIONS IN IMPROVING CART CELL THERAPY IN SOLID TUMORS BEYOND THYROID CANCER.