Advance-CTR Pilot Projects Program (2018)
"Enhance Antitumor Immunity via Modulating Myeloid-Derived Suppressor Cells"
Immune checkpoint blockade therapy (ICBT) targeting programmed cell death protein 1 (PD-1), has shown promising efficacy in treating advanced melanoma. However, significant responses or complete tumor rejection remain restricted to a minority of patients even a combination immune checkpoint blockade (ICB) regimen is applied. Immunosuppressive tumor microenvironment (TME) in established tumors, the major reason for immune escape and treatment failure, significantly diminishes the ICB-mediated rejuvenation of exhausted T cells, causing ICB resistance. Novel therapeutic strategies to rescue suppressive TME is thereby in critical demand. Myeloid-derived suppressive cells (MDSCs) are immature myeloid cells that suppress the host immunity and various T-cell functions. We aim to rescue tumor-induced immunosuppression by endogenous MDSC modulation and enhance ICBT-directed antitumor T-cell responses for melanoma. We hypothesize that MDSC modulation via Gr-1 targeted chemo/gene-loaded nanoparticles enhances antitumor T-cell responses induced by immune checkpoint blockade therapy for melanoma. Gemcitabine and STAT3 inhibition mediated reduction in MDSCs is expected to prevent the inactivation and exhaustion of CD8+ T cells induced by ICBT.