Author of

• 25802

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  OA06 - Early Stage Lung Cancer: Outcomes and Interventions (ID 902)

  • Event: WCLC 2018
  • Type: Oral Abstract Session
  • Track: Treatment of Early Stage/Localized Disease
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/24/2018, 13:30 - 15:00, Room 202 BD

  • 25803

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    OA06.01 - Case-Series Study in Ever- and Never-Smoking Females and Males with NSCLC: Exposures, Tumor Factors, Biology and Survival (SWOG S0424) (ID 14526)

    13:30 - 13:40  |  Author(s): Robert A. Kratzke
    • Abstract
    • Presentation
    • Slides

    Background
    Sex differences in non-small cell lung cancer (NSCLC) susceptibility, tumor biology and survival have been retrospectively reported. We conducted a prospective, case-series intergroup study (SWOG S0424) in 4 cohorts of females (F) and males (M), ever-smokers (ES) and never-smokers (NS) with newly-diagnosed stages I-III NSCLC. This is the first overall survival (OS) report. a9ded1e5ce5d75814730bb4caaf49419 Method
    Patients were accrued at US sites via SWOG/NCI-CTSU. A questionnaire of demographics and exposures (tobacco, environmental, reproductive, hormonal); stage and histology data; treatment; and OS were obtained. Tumor tissue was submitted for EGFR, RAS and p53 mutations. Nuclear and cytoplasmic estrogen receptor (ER) alpha and beta were measured (Cheng, JNCI 2017). Kaplan-Meier (KM) curves and OS modeled using Cox proportional hazards were examined. The NS cohorts remained open longer to maximize accrual. Patients were followed 5 years for OS or until death. 4c3880bb027f159e801041b1021e88e8 Result
    The accrual goal of 981 was achieved from 10/2005-3/2011. Evaluable cases were FES, n=337; MES, 383; FNS, 188; MNS, 49 (MNS under-accrued despite extension). The 4 cohorts differed significantly in demographics, tumor stage, histology, mutational profile (overall, by histology), ER expression, lifestyle factors and exposures. KM curves showed MNS/MES had overlapping OS and FNS/FES had significantly better OS. Five-year estimates were FNS, 73%; FES, 69%; MNS, 58%; MES, 52%. Markedly improved OS for females persisted after adjusting for other factors. Four multivariate OS models were constructed: all patients (model 1) and women only (model 2), each with mutations and ER expression added (models 3, 4). Model 1: better OS for females (HR 0.56, p <.001); higher BMI (continuous, HR 0.98, p=0.045); and adenocarcinoma, BAC, large cell (all vs squamous, HRs 0.84, 0.48, 0.57); worse OS for stages II and III (HRs 1.87, 3.76: each p<.001) and greater age. Model 2: worse OS if ES (HR 1.48, p=0.05), higher stages; histology and hormonal exposure variables were not significant. Model 3: better OS if EGFR mutation (HR 0.53, p=0.013), female, stage I, higher BMI or greater height; worse OS if p53 mutation, higher ER-alpha cytoplasmic or ER-beta nuclear H-scores. Model 4: worse OS if higher stage, p53 mutation or ER-alpha cytoplasmic H-score; EGFR mutation lost significance. 8eea62084ca7e541d918e823422bd82e Conclusion
    Sex, histology, mutations and exposures impacted OS, with dramatically better OS for females regardless of the analysis/model. Hormonal influences (persistent association of ER-expression with OS) were independently significant. Despite adjustments, favorable female survival could not be explained away. Randomized studies should stratify by sex and validation analyses should be conducted in targeted therapy and immunotherapy trials.
    
    SUPPORT: NIH/NCI grants R01CA106815, U10CA180888, U10CA180819 and UG1CA189974. 6f8b794f3246b0c1e1780bb4d4d5dc53

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• 25955

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  P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)

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

  • 27439

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    P3.01-83 - Use of Blood Outgrowth Endothelial Cells as a Cellular Carrier for Oncolytic Vesicular Stomatitis Virus in Preclinical Models of NSCLC (ID 12152)

    12:00 - 13:30  |  Author(s): Robert A. Kratzke
    • Abstract
    • Slides

    Background
    

    Oncolytic virus therapy has demonstrated efficacy in numerous tumor models including non-small cell lung cancer. One of the limitations of viral therapy for metastatic lung cancer is that systemic administration can be hindered by complement and antiviral immunity. Thus, we investigated the possibility of using ex-vivo infected blood outgrowth endothelial cells with tumor-homing properties to deliver oncolytic VSV-IFNβ in preclinical models of NSCLC.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    BOECs were obtained from either human donors or C57/Bl6 mice. Cells were confirmed to maintain the BOEC phenotype and growth characteristics. Indiana strains of VSV were engineered to produce GFP or IFNβ and were titered on Vero cells using either plaque assay or limiting dilution assay. Human NSCLC cell lines, H2009 and H2030 were used for in vitro assays. A549 expressing firefly luciferase cells were used to induce lung metastasis in NOD/SCID mice and treated with BOECs, VSV-IFNβ, or BOECs-infected with VSV-IFNβ. Additionally, syngeneic murine adenocarcinoma cell line, LM2 was used in vivo in A/J mice (n=5).

    4c3880bb027f159e801041b1021e88e8 Result
    

    BOEC cells were able to home to metastatic LM2 lung tumors and were retained there for up to 72 hours post-infusion. BOEC cells were retained within lung tumors of mice bearing tumors, but there were none detected in lungs of mice without lung tumors. Both human and murine BOECs could be infected and lysed by VSV-GFP and VSV-IFNβ, however, VSV-IFNβ was attenuated compared to VSV-GFP. Maximal viral titer was obtained at 24 or 48 hours for VSV-GFP and VSV-IFNβ, respectively. Co-culture experiments showed near complete lysis of H2009 cells using infected BOECs. Both H2009 and H2030 cells were lysed efficiently by infected BOECs while naked VSV was completely inhibited in the presence anti-VSV neutralizing antibodies. Using Firefly luciferase-expressing A549 cells, metastatic lung tumors were induced in NOD/SCID mice. Compared to BOEC alone and PBS-treated mice, VSV-IFNβ-infected BOECs resulted in superior antitumor efficacy as measured by luciferase activity (p<0.02). Infected BOECs resulted in superior survival of mice compared to VSV-IFNβ alone (n=10, p<0.05). Using immune competent A/J mice, infected BOECs trended toward improved antitumor efficacy to BOEC alone and intravenous VSV-IFNβ treatment (n=5, p=0.09). Replicating virus was recovered only from lungs of infected BOEC treated mice.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    BOECs can be used as cellular carrier for systemic delivery of oncolytic VSV-IFNβ. For clinical translation, the use of cellular carriers might be an effective method of virotherapy for metastatic NSCLC.

    6f8b794f3246b0c1e1780bb4d4d5dc53

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