The Development Of Biomaterials To Enable Cancer Immunotherapy Triggered By Local Tumor Treatment

Cancer immunotherapy is a kind of treatment strategy that utilizes the host's own immune system to fight against cancer.In the past decade,cancer immunotherapy has made a series of great breakthroughs and become one of the most promising cancer treatment strategies.Among various types of cancer immunotherapies,immune checkpoint blockade(ICB)and chimeric antigen receptor T(CAR-T)cell therapy have achieved unprecedented clinical successes.Despite the promises in cancer immunotherapy,there is still a long way from truly curing cancer.The next stage is to improve the response rate of immunotherapy and reduce the toxic side effects.Recently,the rational design of combination therapy strategy has been proposed to be a potential solution to solve the current problems in cancer immunotherapy.In this Ph D dissertation,we have systematically studied a variety of local cancer therapies and their mediated immunotherapy strategies.We firstly developed a series of integrated nanoscale platforms for locally enhanced internal radiotherapy by the delivery and sensitization of radioisotopes in vivo.Thereafter,we studied the immune response mediated by various local cancer treatment strategies and their potential for further combination with immunotherapy.The main research results are summarized as follows:Chapter 1:This chapter summarizes the recent research progresses of existing cancer therapies especially cancer immunotherapy and the motivations of the research in this dissertation.Chapter 2:Rhenium-188(¹⁸⁸Re)labeled tungsten disulfide(WS₂)nanoflakes for self-sensitized,near-infrared enhanced radioisotope therapy.WS₂-PEG nanoflakes were labeled with ¹⁸⁸Re with rather high labeling efficiency and great stability via a chelator-free method.Subsequently we for the first time proposed a‘self-sensitization'mechanism,in which the emitted radioactive?-radiation from ¹⁸⁸Re could be absorbed by W to generate secondary electrons to enhance radiation-induced damage to cancer cells.In vivo NIR-enhanced radioisotope therapy with 188 Re-WS²-PEG was finally realized,offering a remarkably improved therapeutic outcome with a rather low radioactivity dose.Chapter 3:Highly effective radioisotope cancer therapy with a non-therapeutic isotope delivered and sensitized by nanoscale coordination polymers.Polyethylene glycol(PEG)-modified nanoscale coordination polymers(NCPs)composed of High-Z element hafnium(Hf⁴⁺)and chelating molecule tetrakis(4-carboxyphenyl)porphyrin(TCPP)are prepared via a one-pot reaction.By chelation with the porphyrin structure of TCPP,such Hf-TCPP-PEG NCPs could be easily labeled with ^99mTc4+.Interestingly,Hf,as a high-Z element in such ^99mTc-Hf-TCPP-PEG NCPs,could endow nontherapeutic ^99mTc with the therapeutic function of killing cancer cells based on our previous research.With efficient tumor retention,our ^99mTc-Hf-TCPP-PEG NCPs offer exceptional therapeutic results in eliminating tumors with moderate doses of ^99mTc after either local or systemic administration.Chapter 4:Combined local immunostimulatory radioisotope therapy and systemic immune checkpoint blockade imparts potent antitumor responses.We synthesize a sodium alginate formulation containing catalase(Cat)labelled with the therapeutic ¹³¹I radioisotope.On injection,the soluble alginate rapidly transforms into a three-dimensional network structure in the presence of endogenous Ca2+,fixing¹³¹I-Cat within the tumors.Through local injection,our sodium alginate composition enables complete tumor elimination at low radioactivity doses in mouse and rabbit xenografts and in patient-derived mouse xenografts.By further introducing the immunomodulator Cp G oligonucleotide and in combination with immune checkpoint blockade,our strategy can not only effectively eliminate primary solid tumors,but also inhibit metastasis and prevent tumor recurrence.Our proposed RIT–immunotherapy approach to achieve systemic therapeutic responses by local treatment could have clinical potential for next-generation cancer therapy.Chapter 5:Iron nanoparticles for low-power local magnetic hyperthermia in combination with immune checkpoint blockade for systemic antitumor therapy.Pure iron nanoparticles(Fe NP)are prepared by a chemical reduction method33,34 and then functionalized with polyethylene glycol(PEG)/dopamine(DA)cografted polymer.The obtained PEGylated Fe NPs could be well dispersed in aqueous solutions with good stability and may be stored in the lyophilized form with a long shelf life before being redispersed and used.Effective MHT ablation of tumors is then achieved,using either locally injected Fe NPs or intravenously injected Fe NPs with the help of locally applied tumor-focused constant magnetic field to enhance the tumor accumulation of those nanoparticles.We further demonstrate that the combination of Fe NP-based MHT with local injection of nanoadjuvant and systemic injection of anticytotoxic Tlymphocyte antigen-4(anti-CTLA4)checkpoint blockade would result in systemic therapeutic responses to inhibit tumor metastasis.This work not only highlights that Fe NPs with appropriate surface modification could act as a supereffective MHT agent but also for the first time report the great promises of combining MHT with immunotherapy.Chapter 6:Localized cock-tail chemo-immunotherapy after in situ gelation to trigger robust systemic antitumor immune responses.We report a‘cock-tail'chemo-immunotherapy strategy by mixing immunogenic cell death(ICD)-inducing chemotherapeutics and immune adjuvants together with alginate(ALG)for localized chemo-immunotherapy.After chemotherapy-induced ICD,the generated tumor-associated antigens in the presence of immune adjuvant would trigger potent tumor-specific immune responses,which would then be further amplified by ICB antibodies to offer potent systemic anti-tumor immune responses to destruct local tumors,eliminate metastatic tumors and inhibit cancer recurrence,as evidenced in treating multiple types of challenging tumor models.All components have been approved for clinical use,so this strategy has great clinical translational potential.Through the development of pharmaceutical technology,we have basically realized the industrialization of related products.In summary,this thesis presents a series of biomaterials-based local cancer therapy and its mediated immunotherapy strategies.We have systematically studied the abscopal effects induced by local treatment strategies and the potential for further combined immunotherapy.Some of the technologies developed in this thesis show great potential in clinical translation.