Development of IG7 as an enhancer of anti-PD-1 cancer immunotherapy

Specific AimsThe emerging clinical success of immune checkpoint inhibitor cancer immunotherapy in the last four years has significantly extended survival of many types of human cancer patientsHowevercolorectal cancerCRCexcept for the small subsetmicrosatellite instableMSICRCstands out as one of the few human cancers where anti PDPD Limmunotherapy has been unsuccessfulThe mechanism under CRC non response to anti PDis unknownIt is generally believed that the expression level of PD Lis a response predictor to anti PDPD LimmunotherapyIn the literaturethe expression levels of PD Lin human CRC cells are controversial and it has been proposed that the lack of PD Lexpression is the underlying mechanism of CRC non response to anti PDPD LimmunotherapyHoweverour preliminary data challenge this notionUsing a recently developed highly specific and FDA approved anti PD LmAbwe have demonstrated that PD Lis abundantly expressed in tumor cells and myeloid derived suppressor cells in human colon carcinomaFurthermoreour preliminary data demonstrated that anti PDand anti PD Limmunotherapy can effectively activate cytotoxic T lymphocytesCTLsIn additionwe have shown that FasL of CTLs is essential for tumor growth control in an orthotopic colon cancer mouse modelBecause CTLs suppress tumor growth through inducing tumor cell deathour observations suggest that CRC resistance to cell death is an underlying mechanism of CRC resistance to anti PDPD LimmunotherapyOur central hypothesis is that CRC apoptosis resistance is an underlying mechanism of human CRC nonresponse to anti PDimmunotherapy and ceramide analog IGis effective in potentiating CRC to FasLinduced apoptosis by anti PDantibody activated CTLsWe will test this hypothesis in this research project by pursuing two specific aimsdetermine the efficacy of IGin promoting Fas clustering and FasLinduced apoptosis in colon carcinoma cells in vivoanddetermine whether IGincreases the efficacy of anti PDimmunotherapy to suppress human colon carcinoma in vivoSuccessfully completion of the proposed studies has the potential to develop IGas a potentiating agent to overcome human colon cancer no response to anti PDimmunotherapy Project NarrativeSuccessful completion of the proposed studies has the potential to develop IGas an enhancer of antiPDimmunotherapy to suppress colorectal cancer in human patients