Antigen-presenting cells (APCs) play a critical role in initiating and regulating the immune response against cancer cells by presenting tumor-specific antigens to T cells. Immunotherapy is providing tremendous promise in the new era of cancer treatment.

Checkpoint inhibitors and adoptive T cell transfer therapy, for example, have shown improved patient survival in melanoma, non-small cell lung cancer, and renal cell cancer patients. However, a growing body of evidence suggests that the tumor microenvironment is profoundly immunosuppressive.

The ability to deliver immunostimulants to the tumor site to mitigate local immune tolerance is crucial for inducing sustained antitumor immunity while reducing systemic toxicity. In contrast to systemic immunotherapy, intratumoral injection of immunomodulators is intended to focus the immune response locally on the malignancy and the affected draining lymph nodes.

Given the heterogeneous nature of tumor antigens, intratumoral immunotherapy may arouse a polyclonal antitumor immune response in situ against diverse cancer targets. Immunostimulants such as cGAMP (cyclic guanosine monophosphate–adenosine monophosphate) target APCs to activate the stimulator of interferon genes (STING) pathway.

Although injected immunotherapy approaches are attractive, only a fraction of patients benefit due to limited effects on distant, uninjected tumor sites. Additionally, commonly used immunostimulants such as CpG and cGAMP are susceptible to degradation and exhibit limited cellular penetration, requiring high concentrations to achieve adequate biological activity.

To overcome these limitations, the inventors have developed an inhalable nanoparticle-immunotherapy system targeting pulmonary APCs to enhance immune responses against lung metastases in breast cancer.

Technology Overview

The inventors propose a nanotechnological approach based on inhalation of lipid nanoparticles containing therapeutic nucleic acids that target APCs for the treatment of lung metastases occurring in breast cancer patients at relapse.

Specifically, aerosolized liposomes are loaded with the STING agonist cyclic guanosine monophosphate–adenosine monophosphate (NP-cGAMP), enabling rapid distribution to both lungs bearing multifocal metastases in mouse models.

Phosphatidylserine (PS) on the outer layer of the liposome facilitates preferential uptake by alveolar macrophages and dendritic cells. Loading cGAMP complexed with calcium phosphate ensures cytosolic release of cGAMP, stimulating the STING pathway and type I interferon production in APCs.

The inventors demonstrated that inhalation of NP-cGAMP enhances radiotherapy (RT) in lung metastasis mouse models. Fractionated RT (8 Gy × 3) delivered to one lung, combined with NP-cGAMP inhalation, controlled metastases in both irradiated and non-irradiated lungs, demonstrating an abscopal effect.

Further Details

Pending US Utility Patent Application No. 17/601,178 titled “Immunotherapeutic Nanoparticles and Methods Relating Thereto”.

Stage of Development

The inventors have obtained proof-of-concept data demonstrating improved therapeutic outcomes in mouse models.

Benefits

  • Lipid-based nanoparticles are biocompatible and safe, and are prepared using a simple two-step water-in-oil reverse microemulsion method.
  • A nebulizer system enables inhalation of aerosolized NP-cGAMP for rapid, localized delivery to deep-seated multifocal lung metastases and uptake by APCs.
  • NP-cGAMP provides more efficient cytosolic delivery of cGAMP than free cGAMP, enhancing STING pathway activation in APCs.
  • Targeted delivery reduces the risk of T-cell apoptosis associated with excessive, non-targeted STING agonist exposure.
  • Phosphatidylserine-coated nanoparticles facilitate uptake by alveolar macrophages and dendritic cells via PS receptors.

Applications

  • Breast cancer immunotherapy following metastasis to the lungs.

Opportunity

  • The university is seeking to license the technology to companies.
  • Open to collaboration with companies experienced in developing liposomal-grade nanomedicines for cancer treatment.