BackgroundThere has been a noticeable increase in the prevalence of allergy-related disorders (ARDs) in the modern era. Urbanization is believed to be a major environmental risk factor for the onset of ARDs but data from low- to middle-income countries is limited.ObjectiveOur purpose was to assess the prevalence of ARDs and atopy among a population of rural Ethiopian school children and identify environmental and lifestyle factors associated with such disorders.MethodsWe performed a cross-sectional study on 541 school-children. An interviewer-led questionnaire administered to the mothers of each participant provided information on demographic and lifestyle variables. Questions on allergic disease symptoms were based on the International Study of Asthma and Allergies in Children (ISAAC) core allergy and environmental questionnaire. Skin prick test for common allergens German cockroach (Blattella germanica) and dust mite (Dermatophagoides) was performed to define atopy. Multiple logistic regression analyses were performed to determine the odds ratio between ARDs and atopy with specific environmental and lifestyle habits.Results541 children responded to the survey questions: the majority of participants were female (60.3%) and aged 10–15 years-old. The prevalence of any ARD was 27%, while the rates of ever-having eczema, rhinitis, and wheeze was found to be 16.8%, 9.6%, and 8.6% respectively. Only 3.6% (19 school-children) tested positive for any skin sensitization. Analysis of associated factors for ARDs found that a family history of allergic disorders (AOR: 2.80; p-value<0.01), use of insecticides (AOR: 2.05; p-value<0.01), and wearing open-toed shoes (AOR: 2.19; p-value = 0.02) were all significantly associated factors. Insecticide use, river-bathing, and infection with intestinal parasites were found to be significantly associated factors for atopy. Other potential risk factors such as frequent use of soap, bacterial infection, and household crowding had no statistical significance.ConclusionOur study suggests that the prevalence of skin sensitization and ARDs in rural populations of developing countries is still relatively low. We identified several possible risk factors for further investigation. Overall, the significance of identified risk factors appears to indicate that genetic predisposition and exposure to environmental pollution are more important to the etiology of ARDs and atopy than specific lifestyle behaviors.

The therapeutic scope of MEK inhibitors (MEKis) is currently limited to use in BRAF mutant melanoma. Therefore, we aim to develop new strategies to extend their usage to MEKi resistant RAS mutant cancers, which represent an unmet clinical need. A strategy we investigated is to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. In Ras mutant murine lung cancers, CH5126766 (CKI27) is novel due to its ability to inhibit both RAF and MEK, preventing the rebound of ERK that normally results from the relief of negative feedback in the MAPK pathway. We observed that CKI27 increased MHC expression on tumor cells and T cell mediated killing. Yet, CKI27 also decreased T cell proliferation, activation, and cytolytic activity. Implementing a break for T cells to recover with intermittent dosing of CKI27 partially relieved these inhibitory effects. Further combination with co-stimulatory agonist antibodies targeting OX40 and GITR completely alleviated these T cell toxicities and increased combination efficacy with checkpoint blockade antibody anti-CTLA-4. Understanding the immunomodulatory effects of combining CKI27 with immunotherapy will elucidate the mechanism behind their increased efficacy. This will allow us to make more informed decisions in dosing regimens, overcoming resistance, and generating long-term immune responses in current and future clinical trials treating patients with RAS mutant cancers.

To enhance the therapeutic scope of MEK inhibitors (MEKis), we aim to develop new strategies to extend their usage to MEKi resistant RAS mutant cancers, which represent an unmet clinical need. CH5126766 (CKI27) binds the allosteric site of MEK to inhibit its kinase activity but is novel due to its interaction with MEK S218 and 228, which blocks their phosphorylation by RAF. CKI27 bound MEK binds to RAF and cannot be released by phosphorylation, thus becoming a dominant negative inhibitor of RAF activation. This prevents the induction of MEK phosphorylation observed with other MEKis. Although this results in more potent tumor control, CKI27 is also capable of inhibiting T cell function because the MAPK/ERK pathway is activated downstream of T cell receptor signaling. We aim to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. We observed that CKI27 increased MHC expression on tumor cells and improved T cell mediated killing. Yet, CKI27 also decreased T cell proliferation, activation, and cytolytic activity. Intermittent administration of CKI27 allowed T cells to recover and partially relieved these inhibitory effects. Further combination with agonist antibodies anti-OX40 and GITR completely alleviated T cell inhibition and increased combination efficacy with immune checkpoint blockade antibody anti-CTLA-4. We also observed an increase in proliferation and T cell activation markers in LLC tumor bearing mice treated with the combination of CKI27, anti-GITR, and anti-CTLA-4. Understanding the immunomodulatory effects of combining CKI27 with immunotherapy will elucidate the mechanism behind this increased efficacy. This will allow us to make more informed decisions in dosing regimens, overcoming resistance, and generating long-term immune responses in future clinical trials treating patients with RAS mutant cancers. Citation Format: Lauren Dong, Hyejin Choi, Sadna Budhu, Isabell Schulze, Svena Verma, Nezar Mehanna, Neal Rosen, Taha Merghoub, Jedd Wolchok. Combining a novel MEK inhibitor with immunomodulation to promote an anti-tumor response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4175.

BackgroundThe therapeutic scope of MEK inhibitors (MEKis) is currently limited to use in BRAF mutant melanoma. Therefore, we aim to develop new strategies to extend their usage to MEKi resistant RAS mutant cancers, which represent an unmet clinical need. In Ras mutant murine lung cancers, CH5126766 (CKI27) is novel due to its ability to inhibit both RAF and MEK, preventing the rebound of p-ERK that normally results from the relief of negative feedback in the MAPK/ERK pathway. However, CKI27 is also capable of inhibiting T cell functions because the MAPK/ERK pathway is activated downstream of T cell receptor signaling. We aim to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy.MethodsTo evaluate the effects of CKI27 on tumor cells and T cells in vitro, we performed flow cytometry, cytokine analysis, and functional co-culture assays. Lewis lung carcinoma (LLC) tumor bearing mice were treated either with CKI27 combined with co-stimulatory agonist antibody targeting GITR and checkpoint blockade antibody targeting CTLA-4 or the appropriate controls to determine efficacy and changes in the tumor microenvironment.ResultsWe observed that CKI27 increased MHC expression on tumor cells and T cell mediated killing. Yet, CKI27 also decreased T cell proliferation, activation, and cytolytic activity. Implementing a break for T cells to recover with intermittent dosing of CKI27 partially relieved these inhibitory effects. Further combination with agonist antibodies anti-OX40 and GITR completely alleviated these T cell toxicities and increased combination efficacy with checkpoint blockade antibody anti-CTLA-4.ConclusionsUnderstanding the immunomodulatory effects of combining CKI27 with immunotherapy will elucidate the mechanism behind their increased efficacy. This will allow us to make more informed decisions in dosing regimens, overcoming resistance, and generating long-term immune responses in current and future clinical trials treating patients with RAS mutant cancers.