L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy
2024
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
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 CO<sub>2</sub>, 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.
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