Co-targeting Ezh2 with PD1 to improve T cell exhaustion reversal and tumor responses

Project Summary In patients suffering from malignancytumor reactive T cells are present in tumor sites but have lost their ability to kill tumor cells due to a dysfunctional state termedexhaustionExhausted T cells are characterized by their inhibition along two axes of functionthe Checkpoint Receptor Axiswith overexpression of inhibitory receptor molecules such as PDTimand Lagand the Cytokine Axiswith suppression of production of Type I cytokinesmost prominently interleukinILThe Checkpoint Receptor Axis has attracted the most focus in clinical settingsFDA has approved anti PDantibody drugsOpdivonivolumaband Keytrudapembrolizumabthat mediate Checkpoint Receptor BlockadeCRBfor the treatment of metastatic melanomanon small cell lung cancer and other tumorsStillonlytoof patients with these cancers respond to CRB therapywith andgtof patients obtaining no benefitindicating considerable room for improvementWe hypothesizebecause anti PDdrugs treat only the Checkpoint Receptor Axis and not the Cytokine Axisthat CRB reversal of exhaustion is less than completeWe further hypothesize that the CRB experience may underrepresent the responses that are possible with a more complete reversal of exhaustion that also addresses the Cytokine Axis concurrentlyOur research recently discovered that transcription factor YYis master regulator of T cell exhaustionmediating both the upregulation of checkpoint receptorsCheckpoint Receptor Axisand the suppression of Type I cytokinesCytokine AxisBalkhi et aliScienceWe show that small molecule inhibitors of Ezhare capable of fully reversing the ILfailure under the Cytokine AxisWith these new discoveriesa perspective is enabled of combining CRB with Ezhinhibitoraddressing both Axes concurrently as envisioned in our Hypotheses abovefor a more complete reversal of exhaustion and improved clinical responsesTo dateour data are confined to the human systemThe goal of this project is to confirm these mechanisms in mouse T cells and to perform in vivo testingi eto determine if Ezhinhibition will synergize with CRB to better restore function to exhausted T cells for superior anti tumor activity over CRB aloneIf our Hypothesis is confirmedhuman clinical trials will follow from which we anticipate Ezhinhibitors will be approved as combination therapy in conjunction with CRB with anti PDimmunotherapy drugs Project Narrative In patients suffering from malignancytumor reactive T cells are present in solid tumors but do not reliably kill tumor cells due to exhaustionTo address exhaustionCheckpoint Receptor BlockadeCRBwith drugse gOpdivonivolumaband Keytrudapembrolizumabhas revolutionized modern cancer therapybut with andgtof treated patients still without benefitThe goal of this project is to achieve a more complete reversal of exhaustion with CRB by the coapplication of Ezhinhibitors to rescue interleukinproduction by exhausted T cells to reinvigorate cancer killing T cells for improved responses