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

Bruna Victorasso, Jardim-Perassi, Pietro, Irrera, Oluwaseyi E., Oluwatola, Dominique, Abrahams, Veronica C., Estrella, Bryce, Ordway, Samantha R., Byrne, Andrew A., Ojeda, Christopher J., Whelan, Jongphil, Kim, Matthew S., Beatty, Sultan, Damgaci-Erturk, Dario Livio, Longo, Kim J., Gaspar, Gabrielle M., Siegers, Barbara A., Centeno, Justin Y.C., Lau, Shari A., Pilon-Thomas, Arig, Ibrahim-Hashim, Robert J., Gillies

Biomedicines |

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.