National Cancer Institute 1R01CA303324-01A1

Nano Electrospun Polymeric Biomaterial Scaffold for GBM Interstitial Immunotherapy

This award funds research on a biodegradable polymer scaffold (Ace-DEX) designed to deliver immunotherapy directly to glioblastoma tumors post-surgery, aiming to enhance immune response and improve treatment outcomes for this aggressive brain cancer.

Description

Nanotechnology is a promising field of research for cancer treatment and can be applied in a scalable method to make polymeric biomaterials on the nanoscale. We propose using the tunable polymer acetalated dextran (Ace-DEX) as a modality to release the toll-like receptor (TLR) 7&8 agonist for the immunotherapy treatment of glioblastoma (GBM). GBM is an aggressive form of primary brain cancer with a dismal prognosis despite therapeutic intervention. Even with standard of care, patients have a median survival of less than one year and only 2% of patients survive out to three years. One promising avenue for the treatment of GBM is the use of immunotherapy. However, many preclinical studies of immunotherapy for the treatment of GBM have been done in the absence of standard-of-care therapy such as resection, which is known to have significant immunological effects. Specifically, tumor resection has been shown to reduce myeloid-derived suppressor cells, recruit effector T-cells, and induce inflammatory cytokines. Appropriate immune-stimulation within this context offers a unique opportunity to tip the balance of the tumor microenvironment away from immunosuppression. Immunostimulatory agents can be locally delivered to the tumor at the time of resection via a biodegradable polymer implant to avoid systemic toxicities. The biopolymer Ace-DEX can be engineered to have specific degradation rates, which is crucial for controlled drug release. This tunability allows for the precise temporal delivery of therapeutic agents, such as the TLR 7&8 agonist resiquimod, directly to the tumor site. Additionally, the thin nature of electrospun Ace-DEX biomaterial prevents mass effects seen with hydrogels and the nanostructure facilitates scaling between animal models, which was a restriction in the development of Gliadel. We hypothesize that the use of our nanoscale biomaterial composed of the biodegradable polymer, Ace-DEX, can effectively deliver resiquimod directly to the tumor which will lead to a robust tumor-specific immune response to prevent GBM recurrence. Understanding the material properties of the Ace-DEX implant (morphology, release and degradation rates) will help to improve this nanosystem for optimum efficacy. The safety and efficacy of the Ace-DEX biomaterial will be evaluated in a clinically relevant orthotopic model of glioblastoma that includes tumor resection. We will also explore local and systemic immune effects induced by the Ace-DEX immunotherapy. Overall, our nanoscale scaffold will deliver immunotherapy directly to the site of the tumor. The use of the biopolymer acetalated dextran (Ace-DEX) is particularly promising due to its tunable properties. We expect that this innovative nanotechnology will fit within GBM current standard of care therapy facilitating its translation to the clinic.

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