# Nanoscale Metal-Organic Frameworks Enable Radiotherapy-Radiodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Generate Tumor Vaccines and Potentiate Immunotherapy of Head and Neck Cancers

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2022 · $494,273

## Abstract

Checkpoint blockade antibodies targeting PD-1 have demonstrated improved survival in metastatic head and
neck squamous cell carcinomas (HNSCC) patients by reactivating effector T cells that have infiltrated the
tumor microenvironment. However, PD-1 blockade still has low overall response rates approximating 18%,
suggesting that the different treatment outcomes are due to intrinsic differences in the patients' diseases, such
as tumor microenvironments. Recently, we have developed a new class of radioenhancers, nanoscale metal-
organic frameworks (nMOFs), that can alter the immune microenvironment. Constructed via coordination
between hafnium-oxo clusters and porphyrin-like molecules, nMOFs generate both hydroxyl radicals and
singlet oxygen in a process termed radiotherapy-radiodynamic therapy (RT-RDT). The objective in this
application is to define the mechanisms by which RT-RDT and nMOF-enabled immunotherapy alter the
immune microenvironment in order to sensitize HNSCCs to checkpoint blockade. Our central hypothesis is
that nMOFs can deliver the CpG oligodeoxynucleotides and synergize with RT-RDT-induced antigen release
and Type I IFN expression, which stimulates CD8+ and CD4+ T cell proliferation and infiltration into HNSCCs to
regress both irradiated and non-irradiated tumors treated with PD-1/PD-L1 blockade. The goal for this
proposed research is to identify a novel therapy and define the mechanisms by which it alters the immune
microenvironment to sensitize HNSCCs and possibly other cancers to current clinical immunotherapies. This
project will use innovative molecularly tunable nMOFs having unprecedented radioenhancement via the unique
RT-RDT mechanism. This proposal is significant because it addresses an unmet need of treating radioresistant
and metastatic HNSCCs both directly via RT-RDT and by acting as an immunostimulant to enhance the
efficacy of existing checkpoint inhibitors. This proposal will test the central hypothesis by pursuing four specific
aims: (1) define the cellular mechanisms of innate immune activation after RT-RDT; (2) determine how RT-
RDT affects the tumor microenvironment in squamous cell cancers; (3) evaluate the contributions of different
immune components on the efficacy of RT-RDT and immunotherapy combinations; and (4) determine effective
therapies for HNSCCs resistant to PD-1/PD-L1 blockade. Aim 1 will treat cells and ex vivo stimulated or
cultured immune components with nMOFs and radiation to determine how RT-RDT initiates STING and Type I
interferon signaling in the tumor microenvironment. Aim 2 will determine how the tumor microenvironment and
extracellular matrix are affected by nMOF-mediated RT-RDT. Aim 3 will evaluate the contribution of different
immune components to the anticancer efficacy of nMOFs. Aim 4 will use primary oral tumor models that are
resistant to PD-1/PD-L1 blockade as a model to identify novel immunotherapy combinations that synergize
with RT-RDT. Ultimately, this project will afford new th...

## Key facts

- **NIH application ID:** 10450090
- **Project number:** 5R01CA253655-03
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Wenbin Lin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $494,273
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450090

## Citation

> US National Institutes of Health, RePORTER application 10450090, Nanoscale Metal-Organic Frameworks Enable Radiotherapy-Radiodynamic Therapy and Deliver CpG Oligodeoxynucleotides to Generate Tumor Vaccines and Potentiate Immunotherapy of Head and Neck Cancers (5R01CA253655-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10450090. Licensed CC0.

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