Abstract
Although checkpoint inhibitors (CPIs) have changed the paradigm of cancer therapy, low response rates and serious systemic adverse events remain challenging. In situ vaccine (ISV), intratumoral injection of immunomodulators that stimulate innate immunity at the tumor site, allows for the development of vaccines in patients themselves. K3-SPG, a second-generation nanoparticulate Toll-like receptor 9 (TLR9) ligand consisting of K-type CpG oligodeoxynucleotide (ODN) wrapped with SPG (schizophyllan), integrates the best of conventional CpG ODNs, making it an ideal cancer immunotherapy adjuvant. Focusing on clinical feasibility for pancreaticobiliary and gastrointestinal cancers, we investigated the antitumor activity of K3-SPG-ISV in preclinical models of pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC). K3-SPG-ISV suppressed tumor growth more potently than K3-ISV or K3-SPG intravenous injections, prolonged survival, and enhanced the antitumor effect of CPIs. Notably, in PDAC model, K3-SPG-ISV alone induced systemic antitumor effect and immunological memory. ISV combination of K3-SPG and agonistic CD40 antibody further enhanced the antitumor effect. Our results imply that K3-SPG-based ISV can be applied as monotherapy or combined with CPIs to improve their response rate or, conversely, with CPI-free local immunotherapy to avoid CPI-related adverse events. In either strategy, the potency of K3-SPG-based ISV would provide the rationale for its clinical application to puncturable pancreaticobiliary and gastrointestinal malignancies.
Highlights
The field of cancer immunotherapy is rapidly evolving
Our results revealed that K3-SPG-In situ vaccine (ISV) monotherapy sufficiently induced systemic and long-lasting memory responses and that it acted synergistically with both systemic administration of checkpoint inhibitors (CPIs) and local administration of a CD40 agonist, another innate immune s timulator[30], establishing the proof of concept for its clinical application in these intractable cancers, for which tumor puncture is a routine clinical technique
In an in vitro human peripheral blood mononuclear cell (PBMC) experiment, enzyme-linked immunosorbent assay (ELISA) analysis showed that K3-SPG produced higher amounts of IFN-α than K3, which was comparable to that produced by D35 (Fig. 1A, left panel)
Summary
The field of cancer immunotherapy is rapidly evolving. The great clinical achievements of antagonizing monoclonal antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1), called checkpoint inhibitors (CPIs), have clearly proven that the immune system is capable of eradicating tumor cells, validating the concept of harnessing the patient’s own immune system to control c ancer[1]. CpG oligodeoxynucleotide (ODN), a ligand for Toll-like receptor 9 (TLR9), stimulates dendritic cells (DCs) to produce cytokines such as type I interferon (IFN) and interleukin (IL)-12, which induce a Th1-type response characterized by IFN-γ production This is a critical step in the activation of naïve T cells to functional antitumor CD8 T cells called cytotoxic T lymphocytes (CTLs), central players in cancer immunity[5–7]. We recently developed a second-generation TLR9 agonist designated as K3-SPG, which is a nanoparticulate K-type CpG ODN (K3) wrapped with the nonagonistic Dectin-1 ligand schizophyllan (SPG)[9] It forms a completely solubilized higher order nano-sized particle. Our results revealed that K3-SPG-ISV monotherapy sufficiently induced systemic and long-lasting memory responses and that it acted synergistically with both systemic administration of CPIs and local administration of a CD40 agonist, another innate immune s timulator[30], establishing the proof of concept for its clinical application in these intractable cancers, for which tumor puncture is a routine clinical technique
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
