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- Title
L-DOS47 Elevates Pancreatic Cancer Tumor pH and Enhances Response to Immunotherapy.
- Authors
Jardim-Perassi, Bruna Victorasso; Irrera, Pietro; Oluwatola, Oluwaseyi E.; Abrahams, Dominique; Estrella, Veronica C.; Ordway, Bryce; Byrne, Samantha R.; Ojeda, Andrew A.; Whelan, Christopher J.; Kim, Jongphil; Beatty, Matthew S.; Damgaci-Erturk, Sultan; Longo, Dario Livio; Gaspar, Kim J.; Siegers, Gabrielle M.; Centeno, Barbara A.; Lau, Justin Y. C.; Pilon-Thomas, Shari A.; Ibrahim-Hashim, Arig; Gillies, Robert J.
- 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.
- Subjects
PANCREATIC cancer; PANCREATIC tumors; TUMOR growth; GASTROINTESTINAL cancer; IMMUNOTHERAPY; UREASE
- Publication
Biomedicines, 2024, Vol 12, Issue 2, p461
- ISSN
2227-9059
- Publication type
Article
- DOI
10.3390/biomedicines12020461