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

doi:10.3390/biomedicines12020461

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

Biomedicines. 2024 Feb 19;12(2):461. doi: 10.3390/biomedicines12020461.

Authors

Bruna Victorasso Jardim-Perassi¹, Pietro Irrera¹, Oluwaseyi E Oluwatola^{2

3}, Dominique Abrahams⁴, Veronica C Estrella¹, Bryce Ordway^{1

5}, Samantha R Byrne², Andrew A Ojeda², Christopher J Whelan^{1

6}, Jongphil Kim⁷, Matthew S Beatty², Sultan Damgaci-Erturk¹, Dario Livio Longo⁸, Kim J Gaspar⁹, Gabrielle M Siegers⁹, Barbara A Centeno¹⁰, Justin Y C Lau¹¹, Shari A Pilon-Thomas², Arig Ibrahim-Hashim¹, Robert J Gillies¹

Affiliations

¹ Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
² Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
³ Department of Molecular Medicine, University of South Florida, Tampa, FL 33620, USA.
⁴ Comparative Medicine, University of South Florida, Tampa, FL 33620, USA.
⁵ Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁶ Department of Biological Sciences, University of Illinois, Chicago, IL 60607, USA.
⁷ Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
⁸ Institute of Biostructures and Bioimaging (IBB), National Research Council of Italy (CNR), 10126 Turin, Italy.
⁹ Helix BioPharma Corp., Bay Adelaide Centre-North Tower, 40 Temperance Street, Suite 2700, Toronto, ON M5H 0B4, Canada.
¹⁰ Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
¹¹ Small Animal Imaging Laboratory (SAIL), H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.

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.

Keywords: L-DOS47; acidosis; immunotherapy; pancreatic cancer; targeted therapy.

Abstract

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