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Nanoscale metal-organic frameworks enhance radiotherapy to potentiate checkpoint blockade immunotherapy.

ABSTRACT: Checkpoint blockade immunotherapy enhances systemic antitumor immune response by targeting T cell inhibitory pathways; however, inadequate T cell infiltration has limited its anticancer efficacy. Radiotherapy (RT) has local immunomodulatory effects that can alter the microenvironment of irradiated tumors to synergize with immune checkpoint blockade. However, even with high doses of radiation, RT has rarely elicited systemic immune responses. Herein, we report the design of two porous Hf-based nanoscale metal-organic frameworks (nMOFs) as highly effective radioenhancers that significantly outperform HfO₂, a clinically investigated radioenhancer in vitro and in vivo. Importantly, the combination of nMOF-mediated low-dose RT with an anti-programmed death-ligand 1 antibody effectively extends the local therapeutic effects of RT to distant tumors via abscopal effects. Our work establishes the feasibility of combining nMOF-mediated RT with immune checkpoint blockade to elicit systemic antitumor immunity in non-T cell-inflamed tumor phenotypes without normal tissue toxicity, promising to broaden the application of checkpoint blockade immunotherapy.

SUBMITTER: Ni K

PROVIDER: S-EPMC6003951 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Nanoscale metal-organic frameworks enhance radiotherapy to potentiate checkpoint blockade immunotherapy.

Ni Kaiyuan K Lan Guangxu G Chan Christina C Quigley Bryan B Lu Kuangda K Aung Theint T Guo Nining N La Riviere Patrick P Weichselbaum Ralph R RR Lin Wenbin W

Nature communications 20180615 1

Checkpoint blockade immunotherapy enhances systemic antitumor immune response by targeting T cell inhibitory pathways; however, inadequate T cell infiltration has limited its anticancer efficacy. Radiotherapy (RT) has local immunomodulatory effects that can alter the microenvironment of irradiated tumors to synergize with immune checkpoint blockade. However, even with high doses of radiation, RT has rarely elicited systemic immune responses. Herein, we report the design of two porous Hf-based na ...[more]

PMID: 29907739

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Project description:Cancer immunotherapy, particularly checkpoint blockade immunotherapy (CBI), has revolutionized the treatment of some cancers by reactivating the antitumor immunity of hosts with durable response and manageable toxicity. However, many cancer patients with low tumor antigen exposure and immunosuppressive tumor microenvironments do not respond to CBI. A variety of methods have been investigated to reverse immunosuppressive tumor microenvironments and turn "cold" tumors "hot" with the goal of extending the therapeutic benefits of CBI to a broader population of cancer patients. Immunostimulatory adjuvant treatments, such as cancer vaccines, photodynamic therapy (PDT), radiotherapy (RT), radiotherapy-radiodynamic therapy (RT-RDT), and chemodynamic therapy (CDT), promote antigen presentation and T cell priming and, when used in combination with CBI, reactivate and sustain systemic antitumor immunity. Cancer vaccines directly provide tumor antigens, while immunoadjuvant therapies such as PDT, RT, RT-RDT, and CDT kill cancer cells in an immunogenic fashion to release tumor antigens in situ. Direct administration of tumor antigens or indirect intratumoral immunoadjuvant therapies as in situ cancer vaccines initiate the immuno-oncology cycle for antitumor immune response.With the rapid growth of cancer nanotechnology in the past two decades, a large number of nanoparticle platforms have been studied, and some nanomedicines have been translated into clinical trials. Nanomedicine provides a promising strategy to enhance the efficacy of immunoadjuvant therapies to potentiate cancer immunotherapy. Among these nanoparticle platforms, nanoscale metal-organic frameworks (nMOFs) have emerged as a unique class of porous hybrid nanomaterials with metal cluster secondary building units and organic linkers. With molecular modularity, structural tunability, intrinsic porosity, tunable stability, and biocompatibility, nMOFs are ideally suited for biomedical applications, particularly cancer treatments.In this Account, we present recent breakthroughs in the design of nMOFs as nanocarriers for cancer vaccine delivery and as nanosensitizers for PDT, CDT, RT, and RT-RDT. The versatility of nMOFs allows them to be fine-tuned to effectively load tumor antigens and immunoadjuvants as cancer vaccines and significantly enhance the local antitumor efficacy of PDT, RT, RT-RDT, and CDT via generation of reactive oxygen species (ROS) for in situ cancer vaccination. These nMOF-based treatments are further combined with cancer immunotherapies to elicit systemic antitumor immunity. We discuss novel strategies to enhance light tissue penetration and overcome tumor hypoxia in PDT, to increase energy deposition and ROS diffusion in RT, to combine the advantages of PDT and RT to enable RT-RDT, and to trigger CDT by hijacking aberrant metabolic processes in tumors. Loading nMOFs with small-molecule drugs such as an indoleamine 2,3-dioxygenase inhibitor, the toll-like receptor agonist imiquimod, and biomacromolecules such as CpG oligodeoxynucleotides and anti-CD47 antibody synergizes with nMOF-based radical therapies to enhance their immunotherapeutic effects. Further combination with immune checkpoint inhibitors activates systemic antitumor immune responses and elicits abscopal effects. With structural and compositional tunability, nMOFs are poised to provide a new clinically deployable nanotechnology platform to promote immunostimulatory tumor microenvironments by delivering cancer vaccines, mediating PDT, enhancing RT, enabling RT-RDT, and catalyzing CDT and potentiate cancer immunotherapy.

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Nanoscale metal-organic frameworks enhance radiotherapy to potentiate checkpoint blockade immunotherapy.

Publications

Nanoscale metal-organic frameworks enhance radiotherapy to potentiate checkpoint blockade immunotherapy.

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