Improving the platelet-mediated immune checkpoint inhibitor delivery for treating triple-negative breast cancer

Project Summary Despite the great success of immune checkpoint inhibitors in treating a subset of cancer patients by blocking PD1/PDL1 pathway, the treatment outcomes in triple-negative breast cancer (TNBC) remain dismal partially due to the immunosuppressive microenvironment and impaired T cell infiltration in the TNBC. We recently developed a platelet-mediated immune checkpoint inhibitor delivery system (designated P-aPDL1) that could efficiently target the post-surgical tumor site and bioresponsively release aPDL1 in the format of platelet-derived microparticles upon the activation of platelets at the tumor site. We have demonstrated the enhanced treatment efficacy against post-surgical B16F10 melanoma and 4T1 TNBC tumor recurrence, while treatment outcomes on the intact non-immunogenic 4T1 TNBC without pre-treatment with surgery remain to be improved. In this proposal, we intend to develop multi-faceted strategies to enhance the treatment efficacy of P-aPDL1 against TNBC through (1) increasing the tumor-selective P-aPDL1 accumulation by triggering a local thrombus formation at the TNBC site; and (2) modulating the immunosuppressive tumor microenvironment through depleting tumor- associated macrophages (TAMs). Specifically, in AIM 1, we will apply a truncated tissue factor-RGD (tTF-RGD) peritumorally or systemically to trigger the local thrombus formation in the tumor tissue and attract the accumulation of P-aPDL1. Both 4T1 TNBC primary and metastatic tumors will be used to evaluate the treatment efficacy. In AIM 2, we will intratumorally inject TAMs-depleting nanoparticles (PLX-NP) to modulate the immunosuppressive microenvironment to facilitate the infiltration of effector T cells to synergize with P-aPDL1 for enhanced treatment efficacy against TNBC. In AIM 3, the combination treatment strategies identified in AIM 1-2 will be evaluated on a fully validated patient-derived xenograft (PDX) TNBC humanized mouse model. This proposal will develop a suite of new combination immunotherapy strategies to increase the anti-tumor efficacy against TNBC and provide significant insights into advancing the current immunotherapeutics for treating other non-immunogenic tumors in the clinic.