Local delivery of immunomodulatory antibodies for gastrointestinal tumors

Abstract

Simple Summary Many types of gastrointestinal tumors, such as gastric, colorectal, and pancreatic cancer, do not respond well to immunotherapies based on the use of antibodies against immune checkpoints, which are injected systemically into patients and generate frequent adverse effects. This review focuses on alternative ways to deliver immunostimulatory antibodies based on gene therapy vectors able to produce them locally at the tumor site. In particular, the use of modified viruses as vectors can induce local inflammation, which contributes to generating stronger antitumor responses. Many preclinical studies show that gastrointestinal tumors could respond better to immunotherapy by using these novel delivery approaches. Cancer therapy has experienced a breakthrough with the use of immune checkpoint inhibitors (ICIs) based on monoclonal antibodies (mAbs), which are able to unleash immune responses against tumors refractory to other therapies. Despite the great advancement that ICIs represent, most patients with gastrointestinal tumors have not benefited from this therapy. In addition, ICIs often induce adverse effects that are related to their systemic use. Local administration of ICIs in tumors could concentrate their effect in the malignant tissue and provide a higher safety profile. A new and attractive approach for local delivery of ICIs is the use of gene therapy vectors to express these blocking antibodies in tumor cells. Several vectors have been evaluated in preclinical models of gastrointestinal tumors to express ICIs against PD-1, PD-L1, and CTLA-4, among other immune checkpoints, with promising results. Vectors used in these settings include oncolytic viruses, self-replicating RNA vectors, and non-replicative viral and non-viral vectors. The use of viral vectors, especially when they have replication capacity, provides an additional adjuvant effect that has been shown to enhance antitumor responses. This review covers the most recent studies involving the use of gene therapy vectors to deliver ICIs to gastrointestinal tumors.