Author of

• 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): Apar Pataer
    • 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.

    6f8b794f3246b0c1e1780bb4d4d5dc53

• 25963

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  P3.09 - Pathology (Not CME Accredited Session) (ID 975)

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

  • 27609

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    P3.09-27 - Histopathologic Parameters Define Features of Treatment Response to Neoadjuvant Chemotherapy in Non-Small Cell Lung Cancer (ID 14257)

    12:00 - 13:30  |  Author(s): Apar Pataer
    • Abstract

    Background
    

    Previous studies indicate that neoadjuvant chemotherapy improves survival in patients with loco-regionally advanced non-small cell lung cancer (NSCLC). The amount of residual viable tumor has been associated with long-term overall survival. This histopathologic measure has potential to become a standard method for evaluation of the effectiveness of neoadjuvant therapy regimens. However, adequate comparison of chemotherapy-treated and untreated lung cancers is lacking. We analyzed histopathologic characteristics of resected NSCLC with and without prior neoadjuvant chemotherapy.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    Histopathologic assessment was performed of specimens obtained from patients enrolled on the immunogenomic lung cancer study (ICON), which integrates clinical, pathologic, immune, genomic and outcome data from surgically resected NSCLC. Cases included material from 10 patients who underwent neoadjuvant chemotherapy and 10 patients treated with primary surgery (adenocarcinoma, n=5; squamous cell carcinoma, n=5; for each cohort). Hematoxylin and eosin-stained tumor sections (mean, 6; range, 3-10) were evaluated and semiquantitatively scored for parameters commonly attributed to treatment response. The percentage of viable tumor was estimated by comparison to the proportion of fibrosis and necrosis on each slide. Additional parameters analyzed included the presence of inflammation, tertiary lymphoid structures (TLS), macrophages, lymphovascular invasion (LVI), cholesterol clefts, giant cells and neovascularization (score 0-3). For each patient, the results for all slides were averaged to determine a mean value. P values were calculated using the Mann-Whitney test.

    4c3880bb027f159e801041b1021e88e8 Result
    

    All histopathologic parameters typically associated with treatment response could also be identified in untreated specimens, albeit in different proportions. Compared to the untreated cohort, samples after chemotherapy were characterized by lower proportion of viable tumor (42.4% vs 67.7%, p=0.04) and higher degrees of fibrosis (46.6% vs 26.6%, p=0.08), and necrosis (11.0 % vs 5.6%, p=0.35). Among the additional parameters, similar scores were seen for inflammation (1.54 vs 1.46, p=0.60), TLS (1.00 vs 0.80, p=0.47), LVI (0.16 vs 0.23, p=0.62), and neovascularization (both 0) while macrophages (0.94 vs 0.12, p=0.20), cholesterol clefts (0.92 vs 0.13, p= 0.03) and giant cells (0.80 vs 0.40, p=0.17) were more common among the neoadjuvant cohort.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Histopathologic variables commonly associated with chemotherapy treatment response can also be identified in treatment naïve lung cancers. However, the amount of viable tumor, fibrosis and cholesterol clefts are parameters strongly associated with neoadjuvant therapy. These results highlight the importance of assessing the type and extent of treatment response. Analysis of larger patient cohorts will reveal potential prognostic value in primary tumors, chemotherapy-treated, and eventually immunotherapy-treated tumors.

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