Alterations of immune response of non-small lung cancer with azacytidine

Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade

First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer.

Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC. We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more. Among the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy. Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533 .)

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Summary Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (, , ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types

Harnessing the IL-7/IL-7R alpha axis to improve tumor immunotherapy.

IL-7 and IL-15 are critical for supporting T cells transferred into a lymphopenic environment. As activated CD8(+) T cells downregulate IL-7R alpha, it is thought IL-15 is more important. However, we find that CD8(+) T cells activated with IL-12 have elevated IL-7R alpha and rely on IL-7 for persistence and antitumor immunity.1132sciescopu

Phase Ib study of anetumab ravtansine in combination with pemetrexed and cisplatin in patients with mesothelin-expressing epithelial mesothelioma or nonsquamous non-small cell lung cancer.

Background: Phase I study with the antibody-drug conjugate anetumab ravtansine demonstrated promising safety and efficacy as monotherapy in mesothelin-expressing tumors, and in particular for patients with advanced metastatic malignant pleural mesothelioma. Pemetrexed in combination with cisplatin is standard for first-line treatment of patients with metastatic mesothelioma and NSCLC. We therefore conducted a phase Ib study to determine the safety, tolerability, and maximum tolerated dose (MTD) of anetumab ravtansine in combination with pemetrexed/cisplatin (Pem/Cis) in subjects with mesothelin-expressing predominantly epithelial mesothelioma or nonsquamous NSCLC. Methods: Patients with histologically confirmed, unresectable, locally advanced or metastatic, mesothelin-expressing predominantly epithelial pleural or peritoneal mesothelioma or nonsquamous NSCLC, who previously failed ≤3 prior lines of chemotherapy, were eligible. Patients were prescreened based on obligatory tumor staining for mesothelin as determined by the Ventana MSLN (SP74) immunohistochemistry assay. Anetumab ravtansine was administered by 1-hour IV infusion on day 1 of every 21-day treatment cycle (Q3W). Pem (500 mg/m ) and Cis (75 mg/m ) were administered as IV infusions Q3W. Serial plasma samples were collected and analyzed for anetumab ravtansine and its components, pemetrexed, total and free platinum. Response to therapy was assessed by RECIST 1.1 and modified RECIST criteria for mesothelioma. Results: As of June 12, 2017, 17 patients had been treated and had received ≥2 cycles of treatment, including 7 patients with pleural mesothelioma, 9 with peritoneal mesothelioma, and 1 with NSCLC. Three patients were treated with anetumab ravtansine 5.5 mg/kg in combination with Pem/Cis with no dose-limiting toxicity (DLT). Six patients were then treated with anetumab ravtansine 6.5 mg/kg in combination with Pem/Cis, again without DLTs. This dose in combination was deemed as the MTD. An additional 8 patients were enrolled in an MTD expansion cohort. Anetumab ravtansine-related adverse events were mainly grade (G)1 and G2. G1/G2 eye toxicities were possibly more frequent with the combination than in historical data. There was one G3 corneal microcystic event and one G3 hypertension. There was a 50% overall response rate (all partial responses) from 16 evaluable patients. Of 13 patients treated at the 6.5 mg/kg MTD dose of anetumab ravtansine in combination with Pem/Cis, the overall response rate was 46%. Based on comparisons to historical data and within-subject comparisons in small number of subjects, clinically relevant PK interaction was not observed. Conclusions: Anetumab ravtansine at 6.5 mg/kg dosed Q3W in combination with standard dosing of Pem/Cis had a manageable toxicity profile without evidence of PK interaction and with early signs of clinical efficacy. Anetumab ravtansine at 6.5 mg/kg in combination with Pem 500 mg/m and Cis 75 mg/m , all administered in a Q3W regimen, is thus feasible and the recommended dose for future study

SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors

The cyclin-dependent kinase 4/6 (CDK4/6) kinase is dysregulated in melanoma, highlighting it as a potential therapeutic target. CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern, and the molecular mechanisms of such resistance remain undefined. We demonstrate that reactivation of mammalian target of rapamycin 1 (mTORC1) signaling through increased expression of the amino acid transporter, solute carrier family 36 member 1 (SLC36A1), drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms: (i) Rb loss, which drives SLC36A1 via reduced suppression of E2f; (ii) fragile X mental retardation syndrome-associated protein 1 overexpression, which promotes SLC36A1 translation and subsequently mTORC1. Last, we demonstrate that a combination of a CDK4/6 inhibitor with an mTORC1 inhibitor has increased therapeutic efficacy in vivo, providing an important avenue for improved therapeutic intervention in aggressive melanoma