Targeting tumor metabolism to improve immunotherapy responses

The acidic microenvironment of solid tumors has suppressing effects on immune cells, accordingly immunotherapy responses. This thesis composed of two main studies as measuring tumor pH with non-invasive methods using MRI/MRSI and targeting tumor acidity to improve immunotherapy responses. Firstly, we developed two different MR imaging techniques to monitor tumor pH. We have shown that the difference in pHs before and after L-DOS47 treatments were statistically significantly different than control mice. To our knowledge this is the first study demonstrates the neutralization ability of proposed drug in in-vivo models. The second aim of this dissertation was to develop combinatorial approaches have potential to be used in the clinic for patient benefits. This includes neutralization oftumoracidityinordertoimproveimmunotherapyresponseswithL-DOS47currently in clinical trials and well tolerated. We have demonstrated in-vivo that L-DOS47 treatment is effective to promote survival when combined with anti-PD1. Overall, under the scope of this study we were able to develop two imaging techniques with MRI to monitor tumor pH and elaborated a combinatorial treatment model in order to boost immunotherapy responses. Isovue, L-DOS47 and anti-PD1 are already approved by FDA to be used in the clinic which makes this study remarkable for a new clinical trial design.