Phase I Trial of Intratumoral Injection of Gene-Modified Dendritic Cells in Lung Cancer Elicits Tumor-Specific Immune Responses and CD8 T-cell Infiltration
ABSTRACT
A phase I study was conducted to determine safety, clinical efficacy, and antitumor immune responses in patients with advanced non-small cell lung carcinoma (NSCLC) following intratumoral administration of autologous dendritic cells (DC) transduced with an adenoviral (Ad) vector expressing the gene (Ad-CCL21-DC). We evaluated safety and tumor antigen-specific immune responses following vaccination (ClinicalTrials.gov: NCT01574222). Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 × 10, 5 × 10, 1 × 10, or 3 × 10 DCs/injection) by CT- or bronchoscopic-guided intratumoral injections (days 0 and 7). Immune responses were assessed by tumor antigen-specific peripheral blood lymphocyte induction of IFNγ in ELISPOT assays. Tumor biopsies were evaluated for CD8 T cells by IHC and for PD-L1 expression by IHC and real-time PCR (RT-PCR). Twenty-five percent (4/16) of patients had stable disease at day 56. Median survival was 3.9 months. ELISPOT assays revealed 6 of 16 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). Patients with increased CD8 T cells following vaccination showed significantly increased PD-L1 mRNA expression. Intratumoral vaccination with Ad-CCL21-DC resulted in (i) induction of systemic tumor antigen-specific immune responses; (ii) enhanced tumor CD8 T-cell infiltration; and (iii) increased tumor PD-L1 expression. Future studies will evaluate the role of combination therapies with PD-1/PD-L1 checkpoint inhibition combined with DC-CCL21 vaccination. .