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S. Sharma

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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)

      14:20 - 15:50  |  Author(s): S. Sharma

      • Abstract
      • Presentation
      • Slides

      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.

      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).

      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).

      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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