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D.A. Elashoff



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    MA09 - Immunotherapy Combinations (ID 390)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      MA09.07 - Phase I Trial of in situ Vaccination with CCL21 Gene-Modified DC Induces Specific Systemic Immune Response and Tumor Infiltrating CD8<sup>+</sup> T Cells (ID 4917)

      15:02 - 15:08  |  Author(s): D.A. Elashoff

      • Abstract
      • Presentation
      • Slides

      Background:
      Intratumoral (IT) infiltration by activated immune effector cells is associated with a significantly better prognosis, however, tumor-associated immune suppression commonly occurs in non-small cell lung cancer (NSCLC). CD8[+ ]T cell or dendritic cell (DC) infiltration is an independent favorable prognostic indicator. CCL21 is a lymphoid chemokine that chemoattracts both lymphocytes and DC. Our aim was to investigate anti-tumor specific systemic immune responses and tumor-infiltrating CD8[+] T cells (CD8[+] TIL) in NSCLC patients in response to in situ vaccination via IT administration of autologous DC transduced with a replication-deficient adenoviral (Ad) vector expressing the secondary lymphoid chemokine (SLC/CCL21) gene. Here, we conducted a phase I trial and evaluated safety and immune responses following in situ vaccination.

      Methods:
      Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 x 10[6], 5 x 10[6], 1 x 10[7], or 3 x 10[7] dendritic cells/injection) by CT- or bronchoscopic-guided IT injection (days 0 and 7). Immune responses were assessed by tumor antigen-specific peripheral blood lymphocyte induction of IFN-γ in ELISPOT assays. Tumor biopsies were evaluated for CD8[+ ]T cells by immunohistochemistry (IHC).

      Results:
      Twenty-five percent (4/16) of patients had stable disease at day 56 follow-up by RECIST criteria. Median survival was 3.9 months. Four possible vaccine-related grade 1 adverse events (AE) occurred in 3 patients with no clear association to dose or schedule; the AE included flu-like symptoms, blood-tinged sputum after each injection, nausea, and fatigue. ELISPOT assays revealed 38% (6/16) of patients had systemic responses against tumor associated antigens (TAA). Tumor CD8[+] T cell infiltration was induced in 54% of subjects (7/13; 3.4 fold average increase in the number of CD8[+ ]T cells per mm[2]). Patients with increased intratumoral CD8[+ ]T cells following vaccination showed significantly increased PD-L1 mRNA expression (p=0.02).

      Conclusion:
      Intratumoral vaccination with Ad-CCL21-DC was well-tolerated and resulted in 1) induction of systemic tumor antigen-specific immune responses and 2) enhanced tumor CD8[+ ]T cell infiltration. DC-CCL21 in situ vaccination may be a promising approach to induce tumor CD8[+ ]T cell infiltration in combination with checkpoint inhibitor therapy.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02b-042 - Reduction in Peripheral Blood Cytokine Levels Observed in EGFR Mutant (EGFRm) Patients Treated with Erlotinib (ID 5403)

      14:30 - 14:30  |  Author(s): D.A. Elashoff

      • Abstract

      Background:
      A retrospective analysis of EGFRm non-small cell lung cancer (NSCLC) patients enrolled on ­­the KEYNOTE-001 trial at UCLA showed a significantly lower objective response rate for those treated with a tyrosine kinase inhibitor (TKI) prior to pembrolizumab than those who were TKI naïve (Garon et al, WCLC 2015). Since nivolumab treated squamous NSCLC patients that had high baseline cytokine levels had a median overall survival almost three times longer than those with low baseline levels (Lena et al, ELCC 2016), we used multiplex cytokine analysis to assess effects of an EGFR TKI on peripheral blood cytokine concentrations.

      Methods:
      Paired baseline and cycle 2 day 1 samples were evaluated in 60 stage IIIb or IV NSCLC patients [EGFRm=12, EGFR wild type (wt)=33, unknown EGFR=15] enrolled on a clinical trial of erlotinib +/- fulvestrant for 30 cytokines [Bio-Rad Bio-Plex Human Cytokine 27-plex and Bio-Plex Pro TGF 3-plex (M500KCAF0Y, 171W4001M)]. Cytokine concentration values were compared between EGFR groups with GEE models. In these models, cytokine values were log-transformed and terms for treatment, EFGR status, and their interaction were included. Age (continuous), sex (binary), smoking status (ever/never), and tumor stage (binary) were also included in the model. R software was used for analyses. A p-value <0.05 was considered statistically significant with no adjustment for multiple comparisons.

      Results:
      For the 12 EGFRm patients treated with erlotinib +/- fulvestrant, 83% (25/30) of the cytokines evaluated showed a quantitative decrease, 17% (5/30) showed a significant decrease, and none showed a significant increase. Similar patterns were not observed in the 33 EGFRwt patients, in whom only 23% (7/30) of the cytokines evaluated showed a decrease, significant in 7% (2/30) with 40% (12/30) showing a significant increase. No clear directional change based on inclusion of fulvestrant in the treatment regimen was seen.

      Conclusion:
      A decrease in peripheral blood cytokine concentrations was observed in EGFRm patients treated with erlotinib +/- fulvestrant but not EGFRwt patients. Although unknown whether these changes persist after erlotinib discontinuation, the decrease in EGFRm patient peripheral blood cytokine levels in response to TKI therapy could contribute to the lower efficacy of anti-PD-1 therapy observed in this population. Future studies will evaluate cytokine levels for EGFRm patients treated with 3[rd] generation TKIs, as well as patients enrolled on a single center investigator-initiated trial evaluating front-line pembrolizumab in EGFRm PD-L1+ patients.