Despite remarkable progress in immunotherapy, definitive biomarkers which can accurately predict clinical response to immunotherapy are still lacking. Resistance to immunotherapy can be largely attributed to extracellular acidity in the tumor microenvironment. We propose to reduce the acidity to improve the response to immunotherapy. We propose to inhibit Vacuolar ATPase that pumps acid out of the tumor cell; Monocarboxylate Transporter 1 that secretes lactic acid into the tumor microenvironment; and Carbonic Anhydrase IX that neutralizes intracellular acids and causes extracellular acidity. We refer to the use of one or more of these inhibitors as "pH-sensitizers" for immunotherapy. We will...

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Despite remarkable progress in immunotherapy, definitive biomarkers which can accurately predict clinical response to immunotherapy are still lacking. Resistance to immunotherapy can be largely attributed to extracellular acidity in the tumor microenvironment. We propose to reduce the acidity to improve the response to immunotherapy. We propose to inhibit Vacuolar ATPase that pumps acid out of the tumor cell; Monocarboxylate Transporter 1 that secretes lactic acid into the tumor microenvironment; and Carbonic Anhydrase IX that neutralizes intracellular acids and causes extracellular acidity. We refer to the use of one or more of these inhibitors as "pH-sensitizers" for immunotherapy. We will combine acidoCEST MRI with hyperpolarized (HP) MR Spectroscopy (MRS) to non-invasively predict clinical response to immunotherapy in a unique melanoma mouse model of progressive immunotherapy resistance. Hyperpolarization increases the signal of conventional MRI by over 10,000 folds. AcidoCEST MRI uses a clinically approved contrast agent to quantitatively measure pHe in the tumor microenvironment, where low pHe represents high acidity. We hypothesize that combining both HP MRS and acidoCEST MRI, we will evaluate the immunotherapy resistance and response in vivo.

Our dual acidoCEST MRI and HP MRS methods can eventually be used to identify melanoma that are likely to be resistant to immunotherapy; to determine the time point when the tumor acidity is sufficiently neutralized to allow for the start of immunotherapy; and to monitor the durability of pH sensitization after starting immunotherapy. Our "biomedical" key innovation is a pH-sensitizer for improving immunotherapy. Our "imaging" key innovation is the use of acidoCEST MRI and HP MRS to measure and monitor pHe and dynamic HP lactate flux during treatment. The combination of these innovations can provide exceptional impact by providing powerful personalized medicine paradigm which can be readily translated to the clinic.

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