DELIVERY OF AN IMMUNOGENIC CELL DEATH INDUCER VIA IMMUNOACTIVE NANOPARTICLES FOR CANCER IMMUNOTHERAPY

  

Cancer immunotherapies have revolutionized anticancer treatment, saving lives by utilizing patients’ immune systems. Immunogenic cell death inducing chemotherapies have recently gained interest as they can not only inhibit the growth of the tumor but also allows the patient to develop a long-lasting immune response to the tumor. However, due to the poor retention of chemotherapies in the tumor and immunosuppressive tumor microenvironment, the activity of immunogenic cell death inducing chemotherapy is limited. To overcome the limitations, I have developed immunofunctional poly(lactic-co-glycolic acid) nanoparticles to enhance the retention of immunogenic cell death inducers at the tumor and increase the recruitment of antigen-presenting cells to the tumor.

In our study, paclitaxel and carfilzomib were determined as immunogenic cell death inducers, supported by in vitro screening of damage-associated molecular patterns and in vivo vaccination study. Both drugs were identified as immunogenic cell death inducing chemotherapy agents. To deliver immunogenic cell death inducers, immunofunctional poly(lactic-co-glycolic acid) nanoparticles were developed by modifying the surface with adenosine triphosphate. The coating of adenosine triphosphate attracted dendritic cells in a concentration gradient manner and improved the stability of adenosine triphosphate against its degrading enzyme. Both paclitaxel and carfilzomib were successfully encapsulated into the developed nanoparticle formulation. Paclitaxel encapsulated nanoparticles were chosen as a lead candidate due to the inherent immunotoxicity of carfilzomib.

Paclitaxel encapsulated nanoparticles coated with ATP effectively suppressed tumor growth in CT26 murine carcinoma and B16F10 murine melanoma. The formulation also increased the immune cell infiltration into the tumor, which may explain the enhanced efficacy of the nanoparticle formulation. Combinational therapy of nanoparticles with anti-PD-1 antibodies significantly increased the complete regression rate in tumor-bearing mice by invigorating the immunosuppressive environment. 

In summary, paclitaxel (an immunogenic cell death inducer) encapsulated in adenosine triphosphate-coated poly(lactic-co-glycolic acid) nanoparticles attracted dendritic cells in a concentration gradient manner and effectively suppressed tumor. Additional anti-PD-1 antibodies further improved the antitumor effect, inducing complete tumor regression in 75% of CT26-bearing mice, by inhibiting the interactions between T cells and immunosuppressive cells (regulatory T cells and myeloid-derived suppressor cells). 

Chapter 1 discusses the current understanding of immunotherapy and delivery systems to enhance immunotherapy. Chapter 2 describes the determination of immunogenic cell death inducers and the development of immunofunctional nanocarrier. The in vivo antitumor efficacy of the nanocarrier was tested in Chapter 3.