Biomaterials For Innovative Combinational Cancer Immunotherapy

In recent years,with the fast development of biotechnology,many new cancer treatment methods have been invented,such as radiofrequency ablation and high intensity focused ultrasound.However,local recurrence and metastasis remain big challenges of such ablation technique in clinic.Therefore,it would be of great importance to explore a combinational therapeutic strategy to inhibit local recurrence and metastasis after tumor ablation.Another breakthrough in cancer therapy is cancer immunology,which aims to re-boost the immune system of the patient to induce tumor-specific response to target tumor cells in vivo.Recently,lots of attention has been paid on immunotherapy.Based on that,we explored several therapeutic strategies.The main results are as follows:Chapter 1:In this chapter,four thermal ablation techniques used in clinical cancer therapy are briefly introduced.Furthermore,the recent developments as well as advantage and drawback of immunotherapy are discussed.Finally,the basis and significance of the research are discussed.Chapter 2:In this chapter,we propose a strategy that combinatorial thermal ablation,adjuvant nanoparticles and immune checkpoint blockade(ICB)to inhibit distant tumor metastasis and recurrence post-ablation using radio-frequency ablation(RFA)or high intensity focused ultrasound(HIFU),which is widely used clinically,inducing vaccine-like antitumor immune responses.The in vivo therapeutic effect as well as the mechanism would be discussed.Chapter 3:Inspired by the excellent inflammatory targeting ability of platelets,here we expect that the monoclonal antibody against programmed-death ligand 1(anti-PD-L1)engineered platelets could inhibit tumor local recurrence effectively,by facilitating transport of anti-PD-L1 antibodies to the ablated area with residue tumors.Using triple-negative breast carcinomas(4T1)bearing mouse model,we proved that antibody-coupled platelets could effectively target incompletely ablated tumor with thermal ablation(TA).The release of anti-PD-L1 is likely triggered by the dissociation of platelets upon the activation.The targeting ability,as well as the therapeutic effect of anti-PDL1-coupled platelets will be discussed.Chapter 4:The erythrocyte or red blood cell(RBC)has become a promising delivery system due to its inherent biocompatibility,which can be metabolized in the body without any safety concern compared with all other synthetic materials.We developed an antigen delivery system based on the nanoerythrosomes extruded from RBCs.Tumor antigens were loaded onto the nanoerythrosomes by fusion of tumor cell membrane-associated tumor antigens with nanoerythrosomes.The splenic APC targeting capacity was not affected by the tumor antigen fusion.We have observed that a significant activation of the immune system by a single dose of tumor antigen loaded nanoerythrosomes(nano-Ag@erythrosome)administration.In addition,synergetic antitumor effects were observed in mouse models against established B16F10 and 4T1 tumor when in combination with anti-programmed death-ligand 1 blockade.We further prepared "personalized nano-Ag@erythrosomes”by fusing tumor tissue after surgery and RBCs from the same body.The“personalized nano-Ag@erythrosomes,could effectively reduce the metastatic tumors and inhibit the tumor recurrence after resection of primary tumorIn summary,this thesis describes several therapeutic strategies based on immunotherapy as well as the surface engineering of platelets and cell membranes.The research results in this paper may provide a basis for the clinical application of tumor immunotherapy in the future.