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Sacha Gnjatic



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    EP1.04 - Immuno-oncology (ID 194)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.04-15 - NSCLC Response Determinants to Chemoimmunotherapy: Deep Profiling of Tumors Following Neoadjuvant Cemiplimab and Chemotherapy (Now Available) (ID 1021)

      08:00 - 18:00  |  Author(s): Sacha Gnjatic

      • Abstract
      • Slides

      Background

      Clinical trials have demonstrated synergistic effects of combination chemoimmunotherapy in patients with locally advanced and metastatic non-small cell lung cancer (NSCLC), however, our understanding is limited as to why and for whom PD-1 blockade with or without chemotherapy is effective, as is our understanding of the mechanism of synergy between these therapies.

      While most patients with resectable NSCLC receive neoadjuvant or adjuvant chemotherapy, this intervention only changes the natural course of disease for ~5% of patients. Early studies have demonstrated major pathologic responses to neoadjuvant immunotherapy ± chemotherapy.

      Method

      To investigate the immunodynamic effect of PD-1 blockade and chemotherapy, and identify potentially more effective immune modifying targets or combinations, we will use novel immunophenotyping platforms to characterize the effect of this combination on the tumor. This trial will enroll 52 patients with Stage Ib-IIIa NSCLC into three cohorts receiving 2 cycles of 1) platinum-doublet chemotherapy, 2) the PD-1 antibody cemiplimab, or 3) combination chemoimmunotherapy. Following surgery, patients will receive additional adjuvant chemoimmunotherapy; in total all patients will receive 4 cycles of standard platinum-doublet chemotherapy and 8 cycles of cemiplimab. All patients will undergo pre-treatment biopsies of their tumor, and blood will be collected at 6 time-points before and after surgery.

      The primary endpoint for this clinical trial is major pathologic response, defined as ≤10% viable tumor within resection. Secondary endpoints include: delay of surgery, disease-free survival, overall response rate, overall survival, measurement of adverse events, and change in CD8 T-cell infiltration.

      Exploratory endpoints include in-depth analysis of the pre-treatment tumor biopsies and post-treatment surgical specimens, and paired blood. We will characterize proteomic and transcriptomic changes in the stromal and immune compartment of tumors at the histologic level using a multiplexed ion-beam imaging (MIBI)—a novel multiplex immunohistochemistry platform capable of analyzing >50 markers on a single section of tissue—and at the single-cell level using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITEseq), a novel platform combining the proteomic data-potential of mass cytometry (CyTOF) and the transcriptomic data-potential of single cell RNA sequencing including TCR sequencing. Feasibility of this multi-pronged approach has been demonstrated on untreated NSCLC (unpublished data, submitted as abstract to WCLC by our group).

      To probe for biomarkers correlating with response or resistance to therapy, we will perform unbiased analysis of peripheral blood lymphoid and myeloid populations by CyTOF, and measure nearly 100 soluble factors in serum using Olink.

      Result

      This trial opened to accrual April 2019.

      Conclusion

      Section not applicable.

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    P1.17 - Treatment of Early Stage/Localized Disease (ID 188)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.17-14 - Prognostic Value of Immune Cell Biomarkers in Surgically Resectable Non-Small Cell Lung Cancer: A Meta-Analysis (Now Available) (ID 2658)

      09:45 - 18:00  |  Author(s): Sacha Gnjatic

      • Abstract
      • Slides

      Background

      Immune cells within the tumor microenvironment (TME) play an important role in the development, progression and outcomes of non-small cell lung cancer (NSCLC). We conducted the first meta-analysis of studies assessing the role of individual immune cells in surgically resected stage I-III NSCLC to evaluate the prognostic value of immune cell biomarkers.

      Method

      PubMed was searched to identify eligible studies assessing clinical outcomes of surgically resected stage I-III NSCLC patients according to immune cell subsets: CD3+ T cells, CD4+ T Helper cells, CD8+ T cytotoxic cells, CD20+ B cells, FoxP3+T Regulatory cells, Natural Killer cells (CD56/CD57+), macrophages (CD68+), and Mast Cells. Meta-analysis was performed using a linear mixed-effects model to determine overall survival (OS) and disease free survival (DFS), and was reported according to whether or not the study adjusted for clinical covariates. I2 was used to assess heterogeneity across studies.

      Result

      42 articles (7,906 patients) were included in this analysis. Higher levels of CD20+ B cells were associated with better OS, while increased FoxP3+ T regulatory cells and Mast Cells were associated with worse OS in unadjusted studies. However, in studies adjusting for clinical variables, CD8+ T cytotoxic cells and Natural Killer cells were also found to be associated with improved OS, while mast cells no longer were significantly detrimental. CD20+ B cells were associated with better DFS in unadjusted studies; in adjusted studies, CD8+ T cytotoxic cells were associated with better survival and FoxP3+ T Regulatory cells were associated with worse survival, with CD20+ B cells no longer significantly associated survival. I2 did not show substantial heterogeneity between studies.

      Table 1: Meta-Analysis Survival Estimates

      OS

      DFS

      Biomarker

      Unadjusted HR (95% CI)

      N, Heterogeneity (%)

      Adjusted HR

      (95% CI)

      N, Heterogeneity (%)

      Unadjusted HR (95% CI)

      N, Heterogeneity (%)

      Adjusted HR

      (95% CI)

      N, Heterogeneity (%)

      CD3+

      T cells

      0.98

      (0.87-1.12)

      6 articles

      I2= 0.00

      0.71

      (0.37-1.37)

      3 articles

      I2= 0.00

      0.98

      (0.86-1.12)

      5 articles

      I2= 0.00%

      -------

      -------

      CD4+

      T Helper cells

      0.64

      (0.37-1.10)

      4 articles

      I2= 13.65

      0.80

      (0.50-1.28)

      4 articles

      I2= 0.00

      0.72

      (0.39-1.32)

      3 articles

      I2= 0.00%

      0.59

      (0.11-3.12)

      1 article

      CD8+

      T Cytotoxic cells

      0.99

      (0.95-1.04)

      14 articles

      I2= 0.00

      0.71

      (0.52-0.96)

      12 articles

      I2= 20.95

      0.94

      (0.77-1.16)

      8 articles

      I2= 16.65%

      0.60

      (0.41,-0.87)

      9 articles

      I2= 20.43%

      CD20+

      B cells

      0.45

      (0.22-0.93)

      5 articles

      I2= 52.29

      0.16

      (0.04-0.64)

      1 article

      0.57

      (0.33,-1.00)

      4 articles

      I2= 0.00%

      0.51

      (0.20-1.32)

      1 article

      FoxP3+

      T Regulatory cells

      1.78

      (1.20-2.64)

      9 articles

      I2= 14.93

      2.38

      (1.56-3.65)

      6 articles

      I2= 0.00

      1.45

      (0.81-2.59)

      3 articles

      I2= 0.00%

      2.07

      (1.10-3.90)

      3 articles

      I2= 0.00%

      Natural Killer cells

      0.66

      (0.35-1.25)

      3 articles

      I2= 13.63

      0.50

      (0.26-0.95)

      4 articles

      I2= 0.00

      1.35

      (0.39-4.66)

      1 article

      0.59

      (0.27-1.28)

      2 articles

      I2= 0.00%

      Macrophages

      1.11

      (0.65-1.90)

      5 articles

      I2= 18.11

      1.04

      (0.69-1.55)

      6 articles

      I2= 0.00

      -------

      -------

      1.88

      (0.87-4.08)

      4 articles

      I2= 43.97%

      Mast Cells

      1.81

      (1.01-3.15)

      3 articles

      I2=0.00

      2.01

      (0.88-3.92)

      3 articles

      I2=43.99

      2.30

      (1.20-4.70)

      1 article

      1.50

      (0.60-3.60)

      1article

      HR= Hazard Ratio, CI = Confidence Interval

      Conclusion

      Immune cell subsets are able to provide prognostic information in early-stage NSCLC undergoing surgical resection. When evaluating these immune biomarkers, adjustment for clinical covariates can have a profound impact on survival estimates.

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