L-DOS47 enhances response to immunotherapy in pancreatic cancer tumor
Jardim-Perassi, B. V.; Irrera, P.; Abrahams, D.; Estrella, V. C.; Ordway, B.; Byrne, S. R.; Ojeda, A. A.; Whelan, C. J.; Kim, J.; Beatty, M. S.; Damgaci-Erturk, S.; Longo, D. L.; Gaspar, K. J.; Siegers, G. M.; Centeno, B. A.; Lau, J. Y. C.; Pilon-Thomas, S. A.; Gillies, R. J.; Ibrahim-Hashim, A.
Show 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 CEACAM6, a cell surface protein 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. Our results demonstrate that combining L DOS47 with anti-PD1 significantly increases the efficacy of anti-PD1 monotherapy, reducing tumor growth for up to 4 weeks.
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