Author of

• 25957

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  P3.03 - Biology (Not CME Accredited Session) (ID 969)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall

  • 27480

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    P3.03-05 - Comparative Transcriptomic Analysis of Lung-iPSC, NSCLC, and SCLC: Potential Implications for iPSC Modeling of Lung Cancer (ID 14212)

    12:00 - 13:30  |  Author(s): David S Schrump
    • Abstract
    • Slides

    Background
    

    In addition to having broad applicability as cellular therapies in regenerative medicine, transplantation and oncology, induced pluripotent stem cells (iPSC) may be useful models for studying a variety of benign and malignant diseases. Presently, limited information is available pertaining to the potential utility of iPSC for investigating epigenetic mechanisms of pulmonary carcinogenesis.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    In the present study, RNA- seq techniques were used to examine gene expression profiles in 2 lung-iPSC (Lu-iPSC) clonesderived from normal human small airway epithelial cells (SAEC), 10 SCLC lines, and 10 NSCLC lines relative to SAEC.

    4c3880bb027f159e801041b1021e88e8 Result
    

    Using criteria of 2 fold change and FDR< 0.05, 6318, 12051, and 6504 genes were differentially expressed in Lu-iPSC, SCLC, and NSCLC lines, respectively. A substantial number of differentially expressed genes (44% total) in Lu-iPSC were unique to these cells. Approximately 1/3^rdof genes differentially regulated in Lu-iPSC were modulated in a histology specific manner. 1515 genes representing 24%, 12%, and 23% of differentially expressed genes in Lu-iPSC, SCLC, and NSCLC lines, respectively, were commonly regulated across Lu-iPSC, SCLC and NSCLC. Top canonical pathways included cell cycle control of chromosomal replication and mitotic roles of Polo-like kinases (up-regulated), and granulocyte adhesion and role of cytokines in mediating communication between immune cells (down-regulated). 3499 genes were uniquely regulated in SCLC and NSCLC. 1937 genes were uniquely modulated in SCLC and Lu-iPSC; top canonical pathways included GABA receptor signaling and CREB signaling in neurons (up-regulated), and TREM1 signaling and IL-15 production (down-regulated). Only 102 genes were uniquely modulated in Lu-iPSC and NSCLC; top canonical pathways included tight junction signaling and hepatic fibrosis/hepatic stellate cell activation (up-regulated) and neurotrophin/TRK signaling and PTEN signaling (down-regulated). Differential gene expression signatures and associated pathways suggested that Lu-iPSC more closely reflect SCLC rather than NSCLC. To further examine similarities in epigenetic regulation of gene expression in Lu-iPSC and lung cancers, RNA-seq was performed on Lu-iPSC grown in the presence or absence of Decitabine (0.1µM x 72h). Expression levels of 885 genes were significantly altered by DAC; inflammatory cascades predominated the top canonical pathways. Additional pathways included nuclear excision repair, cell cycle control, DNA methylation and transcriptional repression, and transcriptional regulation of stem cells.DAC-mediated gene signatures in Lu-iPSC did not appear to overlap with SCLC or NSCLC signatures.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Collectively, these findings have potential implications regarding the use of Lu-iPSC models for examining lung cancer associated epigenetic events, and the development of epigenetic regimens for lung cancer therapy.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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• 25958

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  P3.04 - Immunooncology (Not CME Accredited Session) (ID 970)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall

  • 27538

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    P3.04-27 - An Allogeneic Tumor Cell Lysate Vaccine Induces Immune Responses to Lung Cancer Associated Antigens: Preliminary Results of a Phase II Study (ID 14030)

    12:00 - 13:30  |  Presenting Author(s): David S Schrump
    • Abstract
    • Slides

    Background
    

    Whereas lung cancers often express cancer-germline (CG) protein as well as onco-fetal carbohydrate antigens, immune responses to these antigens are limited in lung cancer patients. This trial was performed to examine if a tumor cell lysate vaccine could induce broad immunity to CG and oncofetal antigens, and to ascertain if metronomic cyclophosphamide and celecoxib (cy/cel) enhances vaccine-induced immune responses.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Freeze-thaw lysates were prepared from H1299 lung cancer cells exhibiting high level CG and oncofetal antigen expression. 11 patients with primary thoracic malignancies (6 NSCLC, 2 SCLC, 2 esophageal cancer, 1 thymoma; median age = 61 y) and 10 patients with extrathoracic neoplasms metastatic to the chest (8 sarcoma, 1 melanoma, 1 RCC; median age = 36 y) rendered NED by conventional therapy were randomized to receive lysate (10 mg protein/vaccine) with Iscomatrix™ adjuvant via deep intradermal injection q month x 6 with or without daily oral metronomic cy/cel. The primary endpoint was serologic response to a panel of purified CG as well as carbohydrate antigens assessed in a blinded manner by ELISA or glycan array techniques, respectively, 1 month after the 6^th vaccination. Immune subsets were assessed in peripheral blood (p-values uncorrected for multiple comparisons). Standard of care imaging studies were obtained at baseline and 1 month after the 3^rd and 6^th vaccinations unless otherwise clinically indicated.

    4c3880bb027f159e801041b1021e88e8 Result
    

    All patients exhibited local inflammatory responses and flu-like symptoms lasting 72-96 hours following vaccinations. There were no dose limiting treatment related toxicities. 14 patients (67%) completed all six vaccinations; 7 patients were removed from study early due to disease recurrence. 8 of 14 patients (4: vaccine alone and 4: vaccine and cy/cel; 57%) exhibited serologic responses to NY-ESO-1. One patient developed antibodies to GAGE7; several patients exhibited reactivity to XAGE and MAGE-C2. Additional serologic responses were observed against Muc1, Muc1Tn, and LSTc. Vaccine therapy decreased percent Tregs (p=0.067), PD-1 expression on Tregs (p=0.023), PD-L1 expression on CD14⁺ monocytes (p=0.0089), PD-L1 expression on classical monocytes (p=0.0159), and PD-L1 expression on intermediate monocytes (p= 0.0031). Cy/cel did not increase immune responses or enhance vaccine-induced alterations in peripheral immune subsets.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    : H1299 lysate vaccines with Iscomatrix™ induce immune responses to CG and oncofetal antigens commonly expressed in lung cancers, and modulate peripheral immune subsets in a manner that may enhance antitumor immunity. These findings support further evaluation of the vaccine in combination with epigenetic agents and immune checkpoint inhibitors for lung cancer therapy.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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