Augmentation of T Cell Function as a Selection Criteria for Chemotherapeutic Treatments

Chemotherapeutic drugs have been widely used in the past as a first-line treatment regimen for many cancer patients. This has been true with the treatment of metastatic melanoma, which has a very poor prognosis as the life expectancy of patients after diagnosis is about six to twelve months. However, in the past decade, significant advances in discovery of targeted molecular drugs and inhibitors such as Vemurafenib, a specific inhibitor that targets a B-Raf gene mutation, have revitalized the landscape of how we approach treatment of patients. Vemurafenib was highly anticipated as more than half of the patients present the mutation; although a dramatic short term success was achieved, tumors often escaped the inhibition through other proliferative pathways. Therefore, we designed synthetic lethality screens that were used to identify small molecule inhibitors (SMI) from a library of compounds and inhibitors that synergized with PLX4720, a chemical analog of Vemurafenib. As recent studies have indicated that the effectiveness of numerous chemotherapies is dependent upon the recruitment of adaptive immune responses, we probed how these combinations of chemotherapies impacted upon T cell function and cytokine expression. Two of 6 inhibitors were found to be detrimental to T cell responses. In contrast, 3 inhibitors were found to improve T cell responses (frequency and function) and promoted expansion of T cells from human tumor samples. In particular, PI-103 and OSU-03012, a PI3K and PDK1 inhibitor respectively, augmented certain key immunological cytokines crucial for immune driven killing of cancerous cells (by increase in interferon-gamma production) and maintenance/survival of T cells. We further present data testing the ability of SMI combinations to act in concert with T cell costimulation (CS) and checkpoint inhibition (CPI) approaches and the capacity of manipulated populations to persist in xenograft models and control xenograft growth. Our data indicate that the immunomodulatory capacity of SMI should be screened and viewed as a selection criteria for single agent therapy and as a component of combination of multi-modal therapies. This approach may become crucial as current patients also undergo, sequentially or simultaneously, actual immunotherapies such as PD-1, PDL-1 and/or CTLA-4 blockade treatments in conjunction with traditional chemotherapies and SMIs.