Enhancing pancreatic cancer immunotherapy: Leveraging localized delivery strategies through the use of implantable devices and scaffolds

Abstract

Pancreatic cancer (PC) remains the predominant type of upper gastrointestinal tract cancer, associated with heightened morbidity and a survival rate below 12%. While immunotherapy has brought about transformative changes in the standards of care for most solid tumors, its application in PC is hindered by the ''cold tumor'' microenvironment, marked by the presence of immunosuppressive cells. Modest response rates in PC are attributed, in part to, the fibrotic stroma that obstructs the delivery of systemic immunotherapy. Furthermore, the occurrence of immune-related adverse events (iRAEs) often necessitates the use of sub-therapeutic doses or treatment discontinuation. In the pursuit of innovative approaches to enhance the effectiveness of immunotherapy for PC, implantable drug delivery devices and scaffolds emerge as promising strategies. These technologies offer the potential for sustained drug delivery directly to the tumor site, overcoming stromal barriers, immunosuppression, T cell exclusion, immunotherapy resistance, optimizing drug dosage, and mitigating systemic toxicity. This review offers a comprehensive exploration of pancreatic ductal adenocarcinoma (PDAC), the most common and aggressive form of PC, accompanied by a critical analysis of the challenges the microenvironment presents to the development of successful combinational immunotherapy approaches. Despite efforts, these approaches have thus far fallen short in enhancing treatment outcomes for PDAC. The review will subsequently delve into the imperative need for refining delivery strategies, providing an examination of past and ongoing studies in the field of localized immunotherapy for PDAC. Addressing these issues will lay the groundwork for the development of effective new therapies, thereby enhancing treatment response, patient survival, and overall quality of life for individuals diagnosed with PDAC.

Keywords: Immunotherapy; Implantable device; Local drug delivery; PDAC; Pancreatic cancer; Scheduling treatments.