In situ vaccination using unique TLR9 ligand K3-SPG induces long-lasting systemic immune response and synergizes with systemic and local immunotherapy

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.

Inhibition of IL-12 heterodimers impairs TLR9-mediated prevention of early mouse plasmacytoma cell growth

“…A therapeutic effect of CpG stimulation on mesothelioma growth has been reported previously in a model of mesothelioma using orthotopic xenografts in immunodeficient mice (28). CpG stimulation has also therapeutic effect on pancreas adenocarcinoma and colorectal cancer models (29). TLR9 agonists have been tested in early human clinical trials, including in combined therapies (30).…”

Toll‐like receptors in health and disease

“…Lindsay et al coloaded the hydrophobic chemotherapeutic drug doxorubicin (DTX) and Incorporation of cholesterol-modified TLR9 agonist in synthetic high-density lipoprotein cholesterol (HDL) nanodiscs, and found that the use of DTX-sHDL/CpG inhibited tumor growth and prolonged animal life. 312,313 These findings showed that TLR9 mediates gastric cancer inflammation, is abundantly expressed in GC samples, and facilitates the migration of cancer cells. 314,315 In addition, the TLR9 rs5743836 and rs187084 polymorphisms were linked to a significant oncogenic risk of gastric cancer.…”

“…Even so, their mechanisms of action must be elucidated for maximum therapeutic benefit 304,305,308 . Moreover, researchers have shown that TLR9 agonists are also highly effective and beneficial when combined with traditional cancer treatment (i.e., radiotherapy or chemotherapy) 312,313 …”

“…coloaded the hydrophobic chemotherapeutic drug doxorubicin (DTX) and Incorporation of cholesterol‐modified TLR9 agonist in synthetic high‐density lipoprotein cholesterol (HDL) nanodiscs, and found that the use of DTX‐sHDL/CpG inhibited tumor growth and prolonged animal life. 312 , 313 …”

Colorectal cancer vaccines: The current scenario and future prospects

“…In situ vaccination is an alternative route of administration in addition to standard subcutaneous and intravenous injections for the early diagnosis and treatment of CRC, which relies on endoscopy-guided puncture. In situ injection of K3-SPG as a monotherapy can fully induce systemic and persistent memory responses, and the combination of systemic administration of check point inhibitors (CPIs) and local administration of CD40 agonists has a synergistic antitumor effect ( 83 ).…”