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Imad Tarhoni



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    OA01 - Precision Medicine and Personalized Therapy for Lung Cancer (ID 1)

    • Event: NACLC 2019
    • Type: Oral Abstract Session
    • Track:
    • Presentations: 1
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      OA01.02 - Prognostic Value of Baseline Autoantibodies in Metastatic NSCLC Patients Receiving PD-/PDL-1 Targeted Immunotherapy   (ID 105)

      14:00 - 15:40  |  Presenting Author(s): Imad Tarhoni

      • Abstract
      • Slides

      Background:
      Immune checkpoint inhibitors targeting either programmed cell death protein-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) have advanced the paradigm for management of Non-small Cell Lung Cancer (NSCLC). However, only a subset of patients showed durable response leaving the majority at risk of progression especially with lack of feasible biomarkers for appropriate selection of candidates. Humoral immunity is involved in tumor-immune interaction by generation of neoantigens associated autoantibodies. These circulating autoantibodies might provide clinically important prognostic information on response to immunotherapy.


      Method:
      Pretreatment sera from metastatic stage NSCLC patients (n=81) receiving non-frontline standard PD-1/PDL-1 targeted immunotherapy as non-frontline were evaluated for autoantibodies using EMD Millipore’s MILLIPLEX® Human Cancer Autoantibody Magnetic Bead Panel. This panel includes Alpha-enolase (ENO1), Cancer/Testis Antigen 1? (CTAG1B/NY-ESO-1), Cyclin-dependent kinase 4 inhibitor A (p16-INK4a), G2/mitotic-specific cyclin-B1 (CCNB1), Galactose-specific lectin-1 (Galectin 1), Galactose-specific lectin-3 (Galectin 3), Heat shock protein 60 (HSP60), Hypoxia-inducible factor 1-alpha (HIF1?), Insulin-like growth factor 2 mRNA-binding protein 2 (IMP-2), Insulin-like growth factor 2 mRNA-binding protein 3 (IMP-3), Mucin 1 (MUC1), Receptor tyrosine-protein kinase (HER2/ErbB2), sex determining region Y (SRY)-box 2 (SOX2), Survivin (Survivin/BIRC5), Tumor protein p53 (p53). The Panel was processed according to manufacturer-defined protocols and read using a Luminex® FLEXMAP 3D®.All statistical relationships were determined using the Log-Rank test in relation to overall survival (OS) and progression-free survival (PFS). Additionally, observed adverse events were correlated to the autoantibody’s levels, excluding any autoimmune preoccupied co-morbidity, and statistically assessed using Mann-Whitney U test.


      Results:
      Baseline level of autoantibodies specific to IMP2 was significantly associated with time to progression (HR=2.28, 95%CI=1.21-4.3, p=0.01), whereas P53(HR=2.05, 95%CI=1-4.17, p=0.049), HIF1?(HR=3.02, 95%CI=1.05-8.65, p=0.04), HSP60(HR=0.39, 95%CI=0.16-0.85, p=0.02,), and CTAG1B/NY-ESO-1(HR=0.29, 95%CI=0.1-0.8, p=0.017) autoantibodies where significantly associated with overall survival. After considering comorbidity, patients who developed treatment associated pneumonitis (n=5) showed lower levels of ENO1, MUC1, and CTAG1B (all p<0.02) compared to the rest of the cohort. Skin adverse events (n=7) were also associated with significantly lower level of MUC1, CTAG1B, and GAL1 (all p<0.02) compared to the rest of the cohort.


      Conclusion:
      Baseline autoantibodies appeared to have a potential benefit in selecting candidates for PD-1/PDL-1 targeted immunotherapy in metastatic NSCLC and in this limited dataset were associated with the development of some autoimmune adverse events. Further studies are ongoing.

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    OA03 - IO Concerns and Targeted Therapies (ID 3)

    • Event: NACLC 2019
    • Type: Oral Abstract Session
    • Track:
    • Presentations: 1
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      OA03.01 - Biomarkers of Autoimmune Toxicity in Metastatic SCLC Patients Receiving PD-1/PDL-1 Targeted Therapy (ID 104)

      09:45 - 11:15  |  Author(s): Imad Tarhoni

      • Abstract
      • Slides

      Background:
      Cancer immunotherapy has resulted in durable responses in patients with metastatic lung cancer. With general unleashing of the immune system to enhance antitumor responses, a consequent, organ-specific immune-related adverse events can be serious, and even life-threatening. Despite the durable benefit of immunotherapy, these adverse events can indicate the cessation of therapy or incur complex management with a multidisciplinary approach. Prognostic biomarkers for treatment toxicity are required for appropriate selection of candidates for immunotherapy.


      Method:
      Serum specimens from previously treated advanced stage SCLC (n=32) were evaluated with 16 soluble checkpoint molecules and immune regulators using the Human Immuno-Oncology Checkpoint Protein Panel (MilliporeSigma). This panel consists of the following targets: B and T Lymphocyte Associated protein BTLA, CD27, CD28, T-cell immunoglobulin and mucin-domain containing-3 TIM-3, HVEM, CD40, GITR, GITRL, LAG-3, TLR-2, PD-1, PD-L1, CTLA-4, CD80/B7-1, CD86/B7-2, and ICOS. All primary data points were collected on a Luminex FLEXMAP 3D® system. Analyte concentrations were calculated from a 7-point curve using a five-parametric fit algorithm (xPONENT® v4.0.3 Luminex Corp., Austin, TX). The Panel was processed according to manufacturer-defined protocols and read using a Luminex® FLEXMAP 3D®. minimum follow up was three months, and the cohort was grouped into two groups; first group who developed ?grade III adverse events (n=10), and a second group who did not develop ?grade III adverse events(n=22). All statistical comparisons were determined using Mann-Whitney U and one way ANOVA test.


      Results:
      Serum level of six soluble immune checkpoints were significantly associated with the development of grade III immune-related adverse events. Development of grade III immune-related adverse events was associated with higher pretreatment serum level of GIRTL, CD80, CD86, and ICOS( p=0.001,0.019,0.04, and 0.035, respectively), and lower pretreatment serum level of CD27 and CD40 in this cohort( p=0.037, and 0.018, respectively).


      Conclusion:
      In this exploratory analysis circulating biomarkers were associated with the development of autoimmune toxicity in small cell lung cancer patients. larger sample series, further development is required.

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    P1 - Poster Viewing (ID 5)

    • Event: NACLC 2019
    • Type: Poster Session
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 10/11/2019, 16:45 - 18:00, Exhibit Hall
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      P1.05 - Clinical Factors Associated with Progression in Previously Treated Patients with Metastatic NSCLC on Anti-PD-1 Therapy (ID 106)

      16:45 - 18:00  |  Author(s): Imad Tarhoni

      • Abstract

      Background:
      Known prognostic indicators for treatment outcomes in patients with metastatic NSCLC include tumor PD-L1 expression, tumor mutational burden (TBM), and neutrophil to lymphocyte ratio (NLR). This study reports patient characteristics associated with rapid progression (defined as progression within 30 days) in 141 patients with metastatic NSCLC who were treated with single-agent immune checkpoint inhibitors (ICI) at a tertiary care center.


      Method:
      A retrospective chart review and analysis of patients with previously treated stage IV NSCLC who received second or third line, single agent ICI was conducted. Pre-treatment (? 6 weeks prior to receiving ICI) values for weight, BMI, and NLR were compared to baseline values at initiation of treatment with ICI and correlated with rapid progression (progression at 1 month) and progression free survival (PFS).


      Results:
      141 patients were included in analysis. Of these, 59% were female, 70% were Caucasian, and 75% were current or former smokers. 85 patients had pre-treatment NLR values and 41% and 28% had NLR >3.5 and >5, respectively. 106 patients had pre-treatment weight and BMI available. Of these, 14% had pre-treatment BMI < 20, and 63% had a negative change in BMI prior to initiation of ICI with 26% of patients having had a >5% weight loss. Weight loss (p = <0.01) on a continuous scale and weight loss >5% (p = <0.01) were significantly associated with shorter PFS. Rapid progression (PFS *<* 30 days) was associated with pre-treatment NLR >3.5 (p = 0.02), increase in NLR from 6 weeks pre-treatment to baseline at initiation of therapy (p = <0.01), BMI decrease >5% (p = <0.01) and weight loss >5% (p = <0.01) prior to initiation of ICI. Rapid progression was additionally associated with pre-ICI changes in NLR, weight, and BMI analyzed as continuous variables (p = <0.01).


      Conclusion:
      This retrospective study identified clinical features of weight change and NLR in the pre-ICI treatment period that were associated with rapid progression on ICI therapy. These parameters should be investigated in the front line population and may have utility in identifying patients that would benefit from intensification of therapy beyond single agent ICI.

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    PD01 - Poster Discussion Session (ID 4)

    • Event: NACLC 2019
    • Type: Poster Discussion Session
    • Track:
    • Presentations: 1
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      PD01.03 - Changes in Immune Checkpoints Landscape Associated with TGF-β Induced EMT in Lung Adenocarcinoma (ID 94)

      15:45 - 16:45  |  Author(s): Imad Tarhoni

      • Abstract

      Background:
      Immune checkpoint inhibitors have advanced the therapeutic approach for metastatic lung cancer with durable responses. Most patients, however, do not respond or develop secondary resistance and experience relapse. Alterations in multiple signaling pathways are involved in resistance to checkpoint inhibition. Dynamic changes in the immune checkpoints landscape in the tumor cell and its surrounding environment might be associated with invasive phenotype, which may also influence the outcome of cancer immunotherapy. This study demonstrates the impact of microenvironmental TGF-? on the expression and/or shedding patterns of immune checkpoint molecules in lung adenocarcinoma cells.


      Method:
      A549 and H358 cells were grown in RPMI-1640 containing 2.5% FBS at two treatment conditions for five days: control (no treatment) versus 20ng/mL TGF-?. Proteins from cell lysates and conditioned media were collected and were tested with the Human Immuno-Oncology Checkpoint Protein Panel (MilliporeSigma). This panel consists of BTLA, CD27, CD28, TIM-3, HVEM, CD40, GITR, GITRL, LAG-3, TLR-2, PD-1, PD-L1, CTLA-4, CD80, CD86, and ICOS. All primary data points were collected via Luminex FLEXMAP 3D system, and concentrations were calculated using a five-parametric fit algorithm (xPONENT v4.0.3 Luminex Corp Austin, TX). Identical cell cultures were performed previously by our group to profile the mRNA using paired-end sequencing on a HiSeq2000 sequencer (Illumina). Analysis to correlate RNA seq data with the proteomics pattern of immune checkpoints was done using R program version 3.5.


      Results:
      BTLA; CD28; HVEM; CD40; GITR; GITRL; LAG-3; TLR-2; PD-1; PD-L1; CD86 were measurable in cell lysates and conditioned media, whereas, CD27, TIM-3, CTLA-4, and CD80 were either untranslated or were below the level of detection. TGF-? induced significantly elevated CD28 total level in both cell lines (p0.02). PD-L1 and CD86 total levels were higher in A549 cells only (all p0.002) which is opposite to the RNA seq changes. HVEM was diminished inboth cell lines (all p0.002). BTLA and LAG-3 decreased in A549 cells; GITR, PD-1, and CD86 were reduced in H358 cels (all p0.02). Cellular GITR and GITRL ere augmented because of a lowered soluble format although the total evel was not significantly changed. CD40 and ICOS total levels were unchanged. These changes were associated with induction of protein activation cascade, humoral and cellular immune response, and extracellular matrix organization pathways (FDR< 0.002) according to RNA seq analysis.


      Conclusion:
      Invasive phenotype induced by TGF-? changes the immune checkpoints dynamics in lung adenocarcinoma cells which might affect the tumor-immune interaction and the outcome of immune checkpoint blockade.