Project Grant F30CA305905

OVERCOMING ANTIGEN-LOW TUMOR ESCAPE IN NON SMALL CELL LUNG CANCER WITH CHIMERIC TCR T CELL THERAPY - ABSTRACT CAR-T CELL THERAPY HAS REVOLUTIONIZED THE TREATMENT OF HEMATOLOGICAL CANCERS BUT HAS YET TO ACHIEVE DURABLE EFFICACY IN MORE COMMON SOLID TUMORS, SUCH AS NON-SMALL CELL LUNG CANCER (NSCLC). IN A PHASE I TRIAL EVALUATING CAR-TS TARGETING THE TUMOR-ASSOCIATED ANTIGEN ROR1, WE OBSERVED LIMITED EFFICACY DUE TO CAR-T EXHAUSTION AND HETEROGENEOUS ROR1 EXPRESSION ON TUMORS, WHICH LED TO THE ESCAPE OF ANTIGENLOW/NULL TUMORS EVEN IN TRANSIENT RESPONDERS. TO ADDRESS THESE CHALLENGES, WE DEVELOPED AN AUTOCHTHONOUS MODEL OF ROR1+ NSCLC (KPROR1), WHICH RECAPITULATES THE SUPPRESSIVE TUMOR MICROENVIRONMENT (TME), HETEROGENEOUS ROR1 EXPRESSION, AND CAR-T EXHAUSTION OBSERVED IN PATIENTS. WE FOUND THAT ENHANCING T CELL FUNCTION BY OVEREXPRESSING THE AP-1 TRANSCRIPTION FACTOR C-JUN IMPROVED RESPONSE TO PD-L1 BLOCKADE BUT FAILED TO PREVENT ESCAPE OF ROR1LOW/NULL TUMORS, EMPHASIZING THE NEED FOR STRATEGIES THAT BOTH PRESERVE CAR-T FUNCTION AND CONTROL ESCAPE OF ANTIGENLOW/NULL TUMORS. TO ENHANCE CAR-T SENSITIVITY, WE ENGINEERED CHIMERIC TCRS (CHTCRS), WHICH FUSE A CAR SINGLE-CHAIN VARIABLE FRAGMENT (SCFV) TO A TCR CONSTANT CHAIN. CHTCRS SHOW SUPERIOR SENSITIVITY TO ANTIGENLOW TUMORS AND OUTPERFORM CAR-TS IN VIVO IN MODELS OF B CELL MALIGNANCIES. MOREOVER, BI-SPECIFIC CHTCRS TARGETING TWO ANTIGENS OUTPERFORM OPTIMIZED BI-SPECIFIC CAR-TS, SUGGESTING THEY MAY BE MORE EFFECTIVE THAN CAR-TS AT CONTROLLING HETEROGENEOUS SOLID TUMORS. HOWEVER, WHILE CHTCRS DO NOT REQUIRE SYNTHETIC COSTIMULATION FOR EFFICACY IN B CELL MALIGNANCIES, THEIR ACTIVITY IN SOLID TUMORS MAY BE LIMITED BY INSUFFICIENT CO-STIMULATION IN THE SUPPRESSIVE TME. TO OVERCOME THIS BARRIER, WE DESIGNED NOVEL CO-STIMULATORY RECEPTORS THAT CONVERT INHIBITORY PVR-TIGIT SIGNALS INTO ACTIVATING SIGNALS AND ENHANCE CHTCR-T FUNCTION IN VITRO. SINCE CO-STIMULATION PARTIALLY RELIES ON AP-1 ACTIVATION, OVEREXPRESSION OF C-JUN COULD FURTHER AMPLIFY THE FAVORABLE EFFECTS OF CO-STIMULATION. I HYPOTHESIZE THAT CHTCR-TS WILL BE MORE SENSITIVE TO ROR1LOW TUMORS IN VIVO THAN CAR-TS, AND THAT CO-EXPRESSION OF CO-STIMULATORY RECEPTORS TARGETING THE PVR/TIGIT AXIS WILL SYNERGIZE WITH C-JUN OVEREXPRESSION TO ENHANCE CHTCR-T ACTIVITY, ENABLING MORE EFFECTIVE CONTROL OF TUMORS WITH HETEROGENEOUS ROR1 EXPRESSION. IN THIS PROPOSAL, I WILL: 1) ASSESS CHTCR-T ACTIVITY AGAINST ROR1LOW TUMORS IN THE KPROR1 MODEL RELATIVE TO CAR-TS AND IDENTIFY BARRIERS TO EFFICACY, AND 2) DETERMINE WHETHER THE CO-STIMULATORY RECEPTORS I DESIGNED SYNERGIZE WITH C-JUN TO ENHANCE CHTCR-T FUNCTION AND RESPONSE TO PD-L1 BLOCKADE. THESE STUDIES WILL REVEAL THE BARRIERS TO CHTCR-T EFFICACY IN VIVO AND POTENTIALLY IDENTIFY STRATEGIES TO CONTROL ESCAPE OF HETEROGENEOUS LUNG TUMORS. THROUGH THIS FELLOWSHIP, I WILL GAIN EXPERTISE IN TUMOR IMMUNOLOGY, COMPUTATIONAL BIOLOGY, AND PRECLINICAL MOUSE MODELS, EQUIPPING ME TO ADVANCE IMMUNOTHERAPIES BY INTEGRATING FUNDAMENTAL RESEARCH WITH CLINICAL PRACTICE.