UCLA researchers have developed a translational immunotherapy platform that leverages nanoparticle-based delivery of tumor-associated signals and immune-stimulatory molecules to drive localized immune activation in metastatic pancreatic cancer. This approach is designed to initiate de novo immune priming and recondition the tumor microenvironment in immune-excluded settings such as liver metastases.
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and treatment-refractory malignancies, with a five-year survival rate below 10%. Metastatic disease, particularly to the liver, presents a major clinical challenge due to limited response to both cytotoxic and immune-based therapies. Although immunotherapy has transformed treatment paradigms in several cancers, PDAC continues to evade immune surveillance through a combination of stromal exclusion, low neoantigen visibility, and active immune suppression.
Roughly 90% of PDAC tumors harbor activating KRAS mutations, which drive tumor growth and immune evasion. These mutations have historically been difficult to target and are associated with poor outcomes. Overcoming this resistance requires new strategies that can activate immune responses locally and overcome the suppressive tumor microenvironment.
There is growing recognition that effective immunotherapy in PDAC will require rational strategies to initiate the cancer immunity cycle, particularly in sites that lack pre-existing immune infiltration. Recent studies suggest that local delivery of tumor antigens in combination with innate immune activation can facilitate antigen presentation, lymphocyte priming, and infiltration into cold tumor beds. However, few approaches have successfully demonstrated the ability to restructure these immune deserts into responsive tissue niches capable of sustaining anti-tumor immunity.
INNOVATION: This platform leverages nanoparticle technology to co-deliver two key components to the tumor environment: a tumor-associated signal (e.g., a cancer-specific antigen) and a stimulatory signal (an agent that activates the immune system). The aim is to simulate a vaccine-like response—alerting the immune system to the presence of cancer while simultaneously triggering localized immune activation.
This approach is designed to initiate the first steps of the cancer immunity cycle by promoting antigen presentation, activating tumor-specific T cells, and supporting their infiltration into immune-excluded tumors such as liver metastases. By converting these immunologically silent regions into immune-active tissue, the platform may sensitize tumors to downstream therapies, including immune checkpoint inhibitors. The modular design of this technology allows adaptation to various tumor types and immunologic payloads, supporting its use in combination strategies across multiple solid tumor indications.
POTENTIAL APPLICATIONS:
- Immunotherapy for KRAS-mutant pancreatic cancer
- Combination therapy for metastatic liver lesions
- Immune modulation in immune-resistant tumor microenvironments
- Nanoparticle-mediated delivery of tumor-associated or immunostimulatory agents
ADVANTAGES:
- Drives local-immune activation in immune-excluded metastatic sites
- Facilitates antigen-specific T-cell priming and infiltration
- Potential synergy with checkpoint blockage or cytotoxic agents
DEVELOPMENT-TO-DATE: Proof-of-concept was demonstrated in vitro using murine and human PDAC cell lines, confirming nanoparticle uptake, antigen presentation, and dose-dependent activation of key immune signaling pathways. In vivo testing in orthotopic and metastatic murine models showed tumor remodeling, increased T-cell infiltration, and lymphoid-like structure formation. Early data indicate potential for durable immune control and synergy with checkpoint inhibitors. Ongoing work focuses on delivery optimization, immune profiling and translational readiness.
Related Papers (from the inventors only):
Chattopadhyay S, Liao YP, Wang X, Nel AE. Use of Stromal Intervention and Exogenous Neoantigen Vaccination to Boost Pancreatic Cancer Chemo-Immunotherapy by Nanocarriers. Bioengineering (Basel). 2023 Oct 16;10(10):1205. doi: 10.3390/bioengineering10101205. PMID: 37892935; PMCID: PMC10604647.
KEYWORDS: Pancreatic cancer, Immune priming, Nanoparticle immunotherapy, KRAS mutation, Liver metastases, Tumor microenvironment, Targeted Immunotherapy, Innate immune activation, Localized immunotherapy, T cell infiltration