Interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α) are key anti- and pro-inflammatory mediators elicited during the host immune response to Mycobacterium tuberculosis (Mtb). Understanding the opposing effects of these mediators is difficult due to the complexity of processes acting across different spatial (molecular, cellular, and tissue) and temporal (seconds to years) scales. We take an in silico approach and use multi-scale agent based modeling of the immune response to Mtb, including molecular scale details for both TNF-α and IL-10. Our model predicts that IL-10 is necessary to modulate macrophage activation levels and to prevent host-induced tissue damage in a granuloma, an aggregate of cells that forms in response to Mtb. We show that TNF-α and IL-10 parameters related to synthesis, signaling, and spatial distribution processes control concentrations of TNF-α and IL-10 in a granuloma and determine infection outcome in the long-term. We devise an overall measure of granuloma function based on three metrics – total bacterial load, macrophage activation levels, and apoptosis of resting macrophages – and use this metric to demonstrate a balance of TNF-α and IL-10 concentrations is essential to Mtb infection control, within a single granuloma, with minimal host-induced tissue damage. Our findings suggest that a balance of TNF-α and IL-10 defines a granuloma environment that may be beneficial for both host and pathogen, but perturbing the balance could be used as a novel therapeutic strategy to modulate infection outcomes.

Purpose Aberrations in the PI3K/AKT/mTOR and MAPK pathways are routinely found in patients with cancer. To date, safe and effective combinations of drugs that hit both pathways concurrently are scarce. Data from Tolcher and colleagues have shown that the combination of trametinib and everolimus is intolerable at the doses and schedules studied in a phase 1 trial for patients with advanced solid tumors. The purpose of this analysis was to determine the tolerability and outcomes for patients prescribed trametinib and everolimus utilized in 2 open trials at our center. Methods A retrospective analysis was performed on 31 patients with various tumor types at the Avera Cancer Institute with approval from the IRB. Patients who received at least one dose of trametinib in combination with everolimus in addition to concurrent therapies were included. Fifteen patients (48%) had undergone ≥ three lines of therapy prior to initiation of trametinib and everolimus. Descriptive statistics were used to determine primary and secondary outcomes. Tolerability was defined as number of dose adjustments or holds in therapy for each regimen. Primary outcome was based on comparisons between tolerability of the drug regimens and the schedule of doses, line of therapy, concurrent cytotoxic agents, and primary tumor type. A secondary outcome calculated the PFS of eligible patients (n=5) who had different trametinib and everolimus regimens. Results Twenty-three patients (74%) tolerated various combinations of trametinib and everolimus, of which 16 received treatment for more than 3 months. Eight patients (26%) discontinued treatment due to adverse events, of which six patients did so within the first 3 months of treatment. Average time to first hold or reduction in therapy due to toxicities from any trametinib and everolimus regimen was 2.5 months. Most common adverse events were fatigue (n=19), mucositis (n=18), and elevated LFT's (n=17). The most common regimen utilized (n=23) was initiated at trametinib 1 mg daily with everolimus 5 mg every Mon, Wed, Fri. Patients on this regimen experienced dose-limiting toxicities at an average of 1.4 months after initiation. Trametinib and everolimus were most commonly started as ≥ the fourth line of therapy. PFS for evaluable patients was 6.5 months; two patients continue to respond. PIK3CA (n=10) and KRAS (n=9) were the most common mutations identified. Conclusion In this analysis, the combination of trametinib and everolimus has shown to be tolerable in many patients with advanced solid tumors, and has also demonstrated clinical efficacy for patients with heavily pre-treated disease. However, the regimens utilized were highly individualized, thus notable variability existed between patient therapies. Therefore, to determine an optimal dose and schedule to evaluate the overall efficacy of trametinib and everolimus combination, an adequately powered and controlled study would be required. Citation Format: Jason Patterson, Cory Perry, Joe Windscheffel, Rachel Elsey, Kirstin Williams, Nandini Dey, Pradip De, Brian Leyland-Jones, Casey Williams. Tolerability and outcomes of trametinib and everolimus combinations in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3891.