Engineering pH switchable cytokines "Swithckines" to assess and overcome acidotic extracellular environment associated resistance to immunotherapies. – SWITCHKINE

Cancer immunotherapies are here to stay. However, only a minority of patients experience durable survival from these therapies, highlighting the urgent need to develop immunotherapies with improved effectiveness and patient response rates. One mechanism used by tumors to evade the immune response is the generation of an acidic tumor microenvironment (TME). To create a more favorable niche for CAR T-cell function, T cell stimulatory cytokines (IL-2, IL-12) based combinatorial approaches are being explored for potentially improved outcomes compared to conventional CAR T-cell products. While these strategies may potentiate CAR T-cell function and efficacy, they may paradoxically increase the risk of adverse events due to increased pro-inflammatory signaling.
Cytokines are pleiotropic that limits their therapeutic use. In previous work, we have demonstrated the use of yeast surface display for engineering novel cytokines with improve specificity. Unpublished work from our laboratory shows besides cell-intrinsic parameters, extracellular acidic pH environment (pHe) such that found in tumor and lymph nodes, inactivates T-cell stimulatory cytokines (IL-2, IL15), by preventing binding to their receptors. Here, we propose to use a yeast-display-based engineering strategy to generate novel pHe switchable IL-2 and IL-15 cytokines, termed as "SwitchKines" that potently activate T cells in acidic niches while exhibiting reduce activity in physiological pH- increasing their therapeutic utility. We will not only gain insights into how acidic pHe alters cytokine-cytokine receptor interactions but will help us to design potent therapies to overcome TME resistance to immunotherapies. We will test the therapeutic efficacy of "SwitchKines" to expand the scope of checkpoint inhibitors and chimeric antigen receptor (CAR)-T-based immunotherapies in therapy-resistant cancer models. This work will revitalize cytokine immunotherapies for treating cancer and autoimmune diseases.