L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy

Abstract

Acidosis is an important immunosuppressive mechanism that leads to tumor growth. Therefore, we investigated the neutralization of tumor acidity to improve immunotherapy response. L-DOS47, a new targeted urease immunoconjugate designed to neutralize tumor acidity, has been well tolerated in phase I/IIa trials. L-DOS47 binds to CEACAM6, a cell-surface protein that is highly expressed in gastrointestinal cancers, allowing urease to cleave endogenous urea into two NH4+ and one CO2, thereby raising local pH. To test the synergetic effect of neutralizing tumor acidity with immunotherapy, we developed a pancreatic orthotopic murine tumor model (KPC961) expressing human CEACAM6. Using chemical exchange saturation transfer–magnetic resonance imaging (CEST-MRI) to measure the tumor extracellular pH (pHe), we confirmed that L-DOS47 raises the tumor pHe from 4 h to 96 h post injection in acidic tumors (average increase of 0.13 units). Additional studies showed that combining L-DOS47 with anti-PD1 significantly increases the efficacy of the anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.

Current and future immunotherapeutic approaches in pancreatic cancer treatment

“…This was experimented on a model of pancreatic tumors in mice, and it was observed that L-DOS47 elevated the extracellular pH of the tumor. When L-DOS47 was used in conjunction with anti-PD-1, it significantly boosted the effectiveness of the monotherapy, leading to a reduction in tumor growth for a duration of up to 4 weeks [ 482 ]. This study paves the way for using L-DOS47 in future clinical trials.…”