Transdermal bicarbonate buffer therapy increases intra-tumoral pH and elicits anti-tumor responses in bladder cancer

Oluwaseyi Oluwatola^1,2Sarah Bazargan²Pietro Irrera²Darwin Chang²Ashley Thomas²Jamie Blauvelt²Matthew S Beatty²MacLean Hall²Christopher J Whelan²Veronica Estrella²Katarzyna Anna Rejniak²Michael Poch²Nathan Fitzsimmons³Ryan Beal³Arig Ibrahim-Hashim⁴Shari Pilon-Thomas^2*

• ¹University of South Florida, Tampa, United States
• ²Moffitt Cancer Center, Tampa, United States
• ³Dyve biosciences, California, United States
• ⁴Sohar University, Sohar, Oman

Tumor acidosis is a hallmark of cancer that leads to abrogation of T cell function and cancer progression. Oral sodium bicarbonate therapy for alkalization of the extracellular tumor pH has shown moderate positive effects in tumor models. However, its applicability in the clinic is very limited due to the unreasonably high dosage required and gastrointestinal disturbances that arise. In this study, we assessed the functional effects of acidity on T cells. We show that acidity alters T cell proliferation, migration and effector functions as well as transcriptional programming. We then tested the potency of a proprietary transdermal formulation, DYV800, containing sodium bicarbonate to increase the extracellular tumor pH (pHe) and augment anti-tumor immune responses in a murine model of bladder cancer. We found that transdermal DYV800 significantly reduced tumor burden and improved antigen-specific CD8+ T cell responses. Chemical Exchange Saturation Transfer Magnetic Resonance Imaging (CEST-MRI) of treated tumors showed an increase in intra-tumoral pH of bladder tumors, and this therapy also alkalizes the urine. The transdermal delivery of DYV800 led to durable anti-tumor immune responses and is more clinically applicable to combat acidity in bladder cancer than oral bicarbonate. Targeting acidosis in the bladder tumor microenvironment has the potential to enhance T cell responses and improve anti-tumor immunity.