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• 25811

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  MA06 - PDL1, TMB and DNA Repair (ID 903)

  • Event: WCLC 2018
  • Type: Mini Oral Abstract Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 AC

  • 25813

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    MA06.02 - Prospective Immunogenomic Profiling of Non-Small Cell Lung Cancer: Genomic and Immune Profiling Updates from Project ICON (ID 13523)

    13:35 - 13:40  |  Author(s): Ismail M Meraz
    • Abstract
    • Presentation
    • Slides

    Background
    

    Our previous work has demonstrated that higher level of genomic complexity is associated with more heterogeneous neoantigen repertoire, suppressed T cell repertoire and postsurgical relapse in localized non-small cell lung cancers (NSCLC) highlighting the complex interaction of tumor molecular and immune landscape and their impact on cancer biology and patient survival. We launched the ICON Project (Immune Genomic Profiling of NSCLC) to prospectively delineate the molecular and immune landscape of early stage NSCLC and their impact on patient survival through a multidisciplinary approach. Here we report the updated genomic and immune analyses.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Surgical specimens from stage I-III NSCLC were subjected to whole-exome and RNA sequencing for mutational analysis, in silico neoantigen prediction and gene expression analysis as well as T cell receptor sequencing, cytometry by time-of-flight and multiplex immunofluorescence staining.

    4c3880bb027f159e801041b1021e88e8 Result
    

    From 2016-2018, 127 patients were accrued and 50 surgical samples have undergone WES, RNAseq, TCR sequencing and immune phenotyping. Median age is 66 yrs (range: 39-86), 52% (26/50) were female and 76% (38/50) former smokers. 76% (38/50) are non-squamous carcinomas and 24% (12/50) squamous cell carcinomas. 34% have stage I disease (17/50), 30% stage II (15/50), 34% stage III (17/50) and 2% stage IV (1/50). The majority of patients had upfront surgery (45/50; 90%). With median follow-up of 19 months, 15 patients have relapsed. Median tumor mutational burden is 7.8mut/Mb and predicted neoantigen burden was 10/sample (range: 0-250). Predicted neoantigen burden is significantly correlated with tumor mutational burden (r=0.41, p=0.002). The most commonly mutated genes are TP53, KRAS, CDKN2A, PIK3CA, EGFR, BRAF, GRIN2A and ATM. C->A transversions and C->T transitions were the most common mutational subtypes. PD-1 expression and regulatory T-cell (CD4+/FoxP3+) infiltration are significantly increased in tumor tissue compared to normal tissue (p=0.003 and p=0.02 respectively), while CD3, CD8, granzyme B and CD45RO are decreased in tumor tissue compared to normal lung.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    NSCLC tumors have an immunosuppressive microenvironment compared to tumor adjacent normal lung tissues. Clinical data will be adequate to conduct genomic and immune profiling comparisons across different clinical subgroups. Mutational and neoantigen profiling are consistent with previously reported studies and correlations between molecular and immune landscapes and its impact on patient survival are ongoing.

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• 25924

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  P1.04 - Immunooncology (Not CME Accredited Session) (ID 936)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall

  • 26441

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    P1.04-08 - Co-Residence of Patient-Derived Immune Cells in Patient-Derived Xenografts from Lung Cancer Patients (ID 11161)

    16:45 - 18:00  |  Author(s): Ismail M Meraz
    • Abstract

    Background
    

    Patient-derived xenograft (PDX) models have been shown to recapitulate many characteristics of human tumors and have been increasingly used for anticancer drug development, molecular characterization of cancer biology, and development of precision therapies. However, because PDXs are grown in immunodeficient mouse strains, they are regarded as inappropriate for preclinical evaluation of anticancer immunotherapy. Here we evaluated whether patient-derived immune cells co-exist in PDXs derived from lung cancer patients.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    First-generation PDX (F1) was established by subcutaneously implanting human tumor tissue into non-obese diabetic-severe combined immunodeficiency (NOD-SCID) mice with a null mutation of the gene encoding for interleukin-2 receptor g (NSG). When the resulting tumors in these mice grew to about 1.5 cm in diameter, we passaged the tumors in NSG or nude mice for subsequent generations. A small piece of these PDX tissues (about 2-3 mm³) were minced into fragments and cultured in media containing human interleukin-2 (IL-2) (2000 -6000 units/ml) for up to 6 weeks. The proliferated lymphocytes for analyzed by fluorescence-activated cell sorting (FACS) with antibodies specific for human immune cell surface markers. The provenance of cultured cells was determined by DNA fingerprinting assay together with patients’ DNA samples from primary tumors and/or peripheral blood mononuclear cells (PBMC).

    4c3880bb027f159e801041b1021e88e8 Result
    

    The mean time of PDX growth in NSG mice before harvesting for culturing tumor-infiltrating lymphocytes (TILs) was 120 days (ranging from 63-292 days). TILs were successfully cultured from 8 of 25 PDXs samples (about 32%), with one from F2 PDXs and 7 from F1 PDXs. TILs from five of those PDXs were predominantly human CD3⁺CD8⁺ T cells (72% -99%), while the remaining three were predominantly human CD19⁺ B cells (77% - 95%). DNA fingerprint analysis showed that genotypes of TILs were identical to patients’ primary tumors and/or PBMC, demonstrating that the TILs were from the same patients as the PDXs. Further analysis showed that CD8⁺ T cells from PDXs were CD45RO⁺, with either CD62L⁺ or CD62L^-.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Patient-derived immune cells co-exist with PDXs in some lung cancer PDX models. Most of those immune cells were CD3⁺CD8⁺ and could be memory T cells. These results suggest that some PDXs might be used for evaluating functions of tumor resident immune cells and/or for evaluating anticancer immunotherapies.

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