Immune checkpoint silencing using RNAi-incorporated nanoparticles enhances antitumor immunity and therapeutic efficacy compared with antibody-based approaches.

Cytotoxic CD8+ T cell-based cancer immunotherapy has been extensively studied and applied, however, tumor cells are known to evade immune responses through the expression of immune checkpoints, such as programmed death ligand 1 (PD-L1). To overcome these issues, antibody-based immune checkpoint blockades (eg, antiprogrammed cell death 1 (anti-PD-1) and anti-PD-L1) have been revolutionized to improve immune responses. However, their therapeutic efficacy is limited to 15%-20% of the overall objective response rate. Moreover, PD-L1 is secreted from tumor cells, which can interrupt antibody-mediated immune reactions in the tumor microenvironment. We developed poly(lactic-co-glycolic acid) nanoparticles (PLGA-NPs) encapsulating PD-L1 small interfering RNA (siRNA) and PD-1 siRNA, as a delivery platform to silence immune checkpoints. This study used the TC-1 and EG7 tumor models to determine the potential therapeutic efficacy of the PLGA (PD-L1 siRNA+PD-1 siRNA)-NPs, on administration twice per week for 4 weeks. Moreover, we observed combination effect of PLGA (PD-L1 siRNA+PD-1 siRNA)-NPs and PLGA (antigen+adjuvant)-NPs using TC-1 and EG7 tumor-bearing mouse models. PLGA (PD-L1 siRNA+PD-1 siRNA)-NPs boosted the host immune reaction by restoring CD8+ T cell function and promoting cytotoxic CD8+ T cell responses. We demonstrated that the combination of NP-based therapeutic vaccine and PLGA (siRNA)-NPs resulted in significant inhibition of tumor growth compared with the control and antibody-based treatments (p<0.001). The proposed system significantly inhibited tumor growth compared with the antibody-based approaches. Our findings suggest a potential combination approach for cancer immunotherapy using PLGA (PD-L1 siRNA+PD-1 siRNA)-NPs and PLGA (antigen+adjuvant)-NPs as novel immune checkpoint silencing agents.

Won JE ，Byeon Y ，Wi TI ，Lee CM ，Lee JH ，Kang TH ，Lee JW ，Lee Y ，Park YM ，Han HD ... -  《Journal for ImmunoTherapy of Cancer》

Stimuli-responsive magnetic silica-poly-lactic-co-glycolic acid hybrid nanoparticles for targeted cancer chemo-immunotherapy.

Chemotherapy and immunotherapy are two important modalities in cancer management. However, due to multiple reasons, a monotherapy is only partially effective. Hence, if used concurrently in targeted and stimuli-responsive manner, it could have been superior therapeutically. To facilitate co-delivery of chemotherapeutic and immunotherapeutic agent to the target cancer cells, engineered nanoparticles, i.e., a pH-responsive polymer PLGA-coated magnetic silica nanoparticles (Fe3O4-SiO2-PLGA-PDA-PTX-siRNA NPs) encapsulating paclitaxel (PTX) and siRNA against programmed cell death ligand-1 (PD-L1) are synthesized and characterized. Developed nanoparticles demonstrated pH-sensitive sustained drug release up to 10 days. In vitro 4T1 cell line studies showed efficient cellular uptake, PD-L1 gene downregulation, and apoptosis. Further, in vivo efficacy studies carried out in the mice model demonstrated a significant reduction of tumor growth following treatment with dual-Fe3O4-SiO2-PLGA-PDA-PTX-siRNA NPs as compared with monotherapy with Fe3O4-SiO2-PLGA-PDA-PTX NPs. The high therapeutic efficacy observed with dual-Fe3O4-SiO2-PLGA-PDA-PTX-siRNA NPs was mainly due to the cytotoxic effect of PTX combined with targeted silencing of the gene of interest, i.e., PD-L1, which in turn improve CD8+ T cell-mediated cancer cell death as evident with increased proliferation of CD8+ T cells in co-culture experiments. Thereby, dual-Fe3O4-SiO2-PLGA-PDA-PTX-siRNA NPs may have a promising anti-cancer treatment potential against breast cancer; however, the beneficial effects of dual loading of PTX + PD-L1 siRNA may be corroborated against other cancer models such as lung and colorectal cancer models as well as in clinical trials.

Gupta A ，Niveria K ，Chandpa HH ，Singh M ，Kumar V ，Panda AK ，Meena J ... -  《-》

siRNA Nanoparticle Targeting PD-L1 Activates Tumor Immunity and Abrogates Pancreatic Cancer Growth in Humanized Preclinical Model.

Jung JY ，Ryu HJ ，Lee SH ，Kim DY ，Kim MJ ，Lee EJ ，Ryu YM ，Kim SY ，Kim KP ，Choi EY ，Ahn HJ ，Chang S ... -  《-》

PLGA Nanoparticles Codelivering siRNAs against Programmed Cell Death Protein-1 and Its Ligand Gene for Suppression of Colon Tumor Growth.

Kwak SY ，Lee S ，Han HD ，Chang S ，Kim KP ，Ahn HJ ... -  《-》

Regulating the immunosuppressive tumor microenvironment to enhance breast cancer immunotherapy using pH-responsive hybrid membrane-coated nanoparticles.

Gong C ，Yu X ，Zhang W ，Han L ，Wang R ，Wang Y ，Gao S ，Yuan Y ... -  《-》