Neutralizing Intratumoral pH May Improve Responses to Immunotherapy

Neutralizing intratumoral pH may help improve responses to immunotherapy and improve outcomes with current targeted therapies, according to a study published March 15, 2016, in the journal Cancer Research.

 Investigators at the Moffitt Cancer Center are reporting that sodium bicarbonate combined with PD-1 or CTLA-4 Inhibitors, or adoptive T-cell transfer may help reduces melanoma and pancreatic tumor growth.

The researchers found that the acidic pH encountered in a tumor microenvironment has significant immunosuppressive effects. In addition, they demonstrated in vitro that acidic pH may profoundly inhibit T-cell responses, including an abrogation of IFNγ and TNFα secretion. They theorize that an acidic environment may lead to a general block of translation of proinflammatory cytokines.

Several therapies that activate the immune system are currently approved or in clinical development, including drugs that target the immune-suppressing proteins PD-1 and CTLA-4. While these agents have shown promising clinical activity, patient response rates still only range from 18% to 27% for anti-PD-1 antibodies  and 11% for anti-CTLA-4 antibodies. It has been suggested that improvements could be made with combination treatments. Researchers wanted to assess how an acidic environment affects immune cell function and the activity of PD-1 and CTLA-4–targeting cancer therapies.

The team treated mice with the neutralizing agent sodium bicarbonate and observed an indirect response. While the sodium bicarbonate itself didn’t have a direct impact on reducing the size of melanoma tumor cells, there was an increase in T cells within the tumor. The ability of sodium bicarbonate to increase levels of T cells in the tumor suggests that it could work in conjunction with PD-1 and CTLA-4 inhibitors to further stimulate the immune system. Treatment with sodium bicarbonate and CTLA-4 or PD-1 inhibitors reduced melanoma and pancreatic tumor growth when compared to single-agent treatment.

Another promising immune therapy is adoptive T-cell therapy, and this showed much higher efficacy in combination with bicarbonate.

“The acidic pH encountered in a tumor microenvironment has significant immunosuppressive effects. By neutralizing this acid with buffers, we were able to improve the response of melanoma and pancreatic tumors to immunotherapy,” said study author Robert Gillies, PhD, chair of the Department of Cancer Imaging and Metabolism at Moffitt Cancer Center, in a news release.

Moffitt researchers plan to initiate a clinical trial to assess if treatment with sodium bicarbonate increases the efficacy of anti-PD1 therapy in pancreatic and melanoma cancer patients. Dr. Gillies and his team have calculated from their mouse studies that the human equivalent dose would be bicarbonate at 800 mg kg⁻¹ d⁻¹. They note that this dose is clinically achievable and report that early-phase I clinical trials of bicarbonate therapy have been conducted.