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Purpose: PD-1/PD-L1 inhibitors are approved for multiple tumor types. However, resistance poses substantial clinical challenges. Patients and Methods: We conducted a phase I trial of CD40 agonist APX005M (sotigalimab) and CSF1R inhibitor cabiralizumab with or without nivolumab using a 3+3 dose-escalation design (NCT03502330). Patients were enrolled from June 2018 to April 2019. Eligibility included patients with biopsy-proven advanced melanoma, non–small cell lung cancer (NSCLC), or renal cell carcinoma (RCC) who progressed on anti-PD-1/PD-L1. APX005M was dose escalated (0.03, 0.1, or 0.3 mg/kg i.v.) with a fixed dose of cabiralizumab with or without nivolumab every 2 weeks until disease progression or intolerable toxicity. Results: Twenty-six patients (12 melanoma, 1 NSCLC, and 13 RCC) were enrolled in six cohorts, 17 on nivolumab-containing regimens. Median duration of follow-up was 21.3 months. The most common treatment-related adverse events were asymptomatic elevations of lactate dehydrogenase (n = 26), creatine kinase (n = 25), aspartate aminotransferase (n = 25), and alanine aminotransferase (n = 19); periorbital edema (n = 17); and fatigue (n = 13). One dose-limiting toxicity (acute respiratory distress syndrome) occurred in cohort 2. The recommended phase 2 dose was APX005M 0.3 mg/kg, cabiralizumab 4 mg/kg, and nivolumab 240 mg every 2 weeks. Median days on treatment were 66 (range, 23–443). Median cycles were 4.5 (range, 2–21). One patient had unconfirmed partial response (4%), 8 stable disease (31%), 16 disease progression (62%), and 1 unevaluable (4%). Pro-inflammatory cytokines were upregulated 4 hours post-infusion. CD40 and MCSF increased after therapy. Conclusions: This first in-human study of patients with anti-PD-1/PD-L1–resistant tumors treated with dual macrophage-polarizing therapy, with or without nivolumab demonstrated safety and pharmacodynamic activity. Optimization of the dosing frequency and sequence of this combination is warranted.

Tumor heterogeneity is a major challenge for cancer treatment, especially due to the presence of various subpopulations with stem cell or progenitor cell properties. In mouse melanomas, both CD34+p75− (CD34+) and CD34−p75− (CD34−) tumor subpopulations were characterized as melanoma-propagating cells (MPC) that exhibit some of those key features. However, these two subpopulations differ from each other in tumorigenic potential, ability to recapitulate heterogeneity, and chemoresistance. In this study, we demonstrate that CD34+ and CD34− subpopulations carrying the BRAFV600E mutation confer differential sensitivity to targeted BRAF inhibition. Through elevated KDM5B expression, melanoma cells shift toward a more drug-tolerant, CD34− state upon exposure to BRAF inhibitor or combined BRAF inhibitor and MEK inhibitor treatment. KDM5B loss or inhibition shifts melanoma cells to the more BRAF inhibitor–sensitive CD34+ state. These results support that KDM5B is a critical epigenetic regulator that governs the transition of key MPC subpopulations with distinct drug sensitivity. This study also emphasizes the importance of continuing to advance our understanding of intratumor heterogeneity and ultimately develop novel therapeutics by altering the heterogeneous characteristics of melanoma.

This study evaluates the use of HMG-CoA reducatase inhibitors, or statins, as an adjunctive to BRAF and MEK inhibition as a treatment in melanomas and other tumors with driver mutations in the MAPK pathway. Experiments used simvastatin in conjunction with vemurafenib and selumetinib in vitro and simvastatin with vemurafenib in vivo to demonstrated additional growth abrogation beyond MAPK blockade alone. Additional studies demonstrated that statin anti-tumor effects appeared to depend on inhibition of isoprenoid synthesis given rescue with add-back of downstream metabolites. Ultimately we concluded that statins represent a possible useful adjunctive therapy in MAPK-driven tumors when given with current approved targeted therapy.

SummaryHow disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability. While common variants from healthy individuals rarely affect interactions, two-thirds of disease-associated alleles perturb protein-protein interactions, with half corresponding to “edgetic” alleles affecting only a subset of interactions while leaving most other interactions unperturbed. With transcription factors, many alleles that leave protein-protein interactions intact affect DNA binding. Different mutations in the same gene leading to different interaction profiles often result in distinct disease phenotypes. Thus disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread.

e14114 Background: Checkpoint inhibitors such as anti-PD1 (aPD1) have revolutionized treatment of metastatic melanoma. However, a large subset of patients receiving such treatment fails to respond to aPD1 monotherapy due to mechanisms such as PD-L1 upregulation within the tumor and T cell exhaustion in the tumor microenvironment. The PGE2/COX2 signaling pathway is one of the pathways implicated in T cell exhaustion and PD1/PD-L1 upregulation and thus represents an attractive pharmacologic target to enhance effects of aPD1 therapy due to the availability and safety of inhibitors such as aspirin or NSAIDs. There is evidence that PGE2/COX2 pathway inhibitors act synergistically with aPD1 therapy in murine melanoma and breast cancer models. Here we aimed to further characterize this synergism using the YUMMER (Yale University Mouse Melanoma Exposed to Radiation) 1.7 model, an irradiated, syngeneic cell line originating from BrafV600E; Pten-/-; and Cdkn2a -/- genetically engineered mouse melanomas. YUMMER1.7 cells implanted into the flanks of C57BL6/j mice show reproducible but partial responses to intraperitoneal aPD1 therapy and thus serves as an ideal platform to study whether concurrent PGE2/COX2 pathway blockade may result in additive effects to aPD1 therapy. Methods: 6-7 week old male C57BL6/j mice (n = 20) were injected with 500K YUMMER1.7 cells and treated with aPD1 therapy alone starting on day 7 after tumor implantation (n = 10) or with aPD1 therapy starting on day 7 in addition to ibuprofen dissolved in drinking water at a concentration of 1 mg/mL started on the day of tumor implantation (n = 10). Using an average daily water consumption estimate of 6 mL/day, this translates to a human equivalent of roughly 1200 mg/day, a moderate dose of ibuprofen. Tumor growth was monitored and tracked to an endpoint of 1cm3. Results: Tumor volume at day 17 significantly differed between the two groups (p < 0.0001). Survival curves were significantly different between the two groups (p < 0.0001); all tumors treated with aPD1 alone grew to endpoint by day 32, while all tumors treated with aPD1 + ibuprofen regressed with 8 out of 10 showing complete regression by day 32. Conclusions: We have shown that ibuprofen strongly synergizes with aPD1 therapy in a murine model of melanoma, complementing existing evidence. This suggests that PGE2/COX2 inhibitors such as NSAIDs, which are over-the-counter agents with a well-studied safety profile, may serve as a promising means of enhancing the response to aPD1 therapies such as nivolumab in melanoma patients who initially fail aPD1 monotherapy.