Phase I Trial of Intratumoral Injection ofCCL21Gene–Modified Dendritic Cells in Lung Cancer Elicits Tumor-Specific Immune Responses and CD8+ T-cell Infiltration

Abstract

Purpose A phase I study was conducted to determine safety, clinical efficacy, and anti-tumor immune responses in patients with advanced non-small cell lung carcinoma (NSCLC) following intratumoral (IT) administration of autologous dendritic cells (DC) transduced with an adenoviral (Ad) vector expressing the CCL21 gene (Ad-CCL21-DC). We evaluated safety and tumor antigen-specific immune responses following in situ vaccination (ClinicalTrials.gov: NCT01574222). Experimental Design Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 × 106, 5 × 106, 1 × 107, or 3 × 107 dendritic cells/injection) by CT- or bronchoscopic-guided IT injections (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) and for PD-L1 expression by IHC and real-time PCR (RT-PCR). Results 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 mm2). Patients with increased CD8+ T cells following vaccination showed significantly increased PD-L1 mRNA expression. Conclusions Intratumoral vaccination with Ad-CCL21-DC resulted in 1) induction of systemic tumor antigen-specific immune responses, 2) enhanced tumor CD8+ T cell infiltration, and 3) 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 in situ vaccination.

The miR-582/CD1B Axis Is Involved in Regulation of Dendritic Cells and Is Associated with Clinical Outcomes in Advanced Lung Adenocarcinoma

“…Recently, a phase I trial of patients with advanced NSCLC suggested that intratumoral vaccination with autologous DCs could increase infiltration of CD8+ T cells into tumors and increase the expression levels of PD-L1 [34].…”

Tissue‐resident innate immunity in the lung

“…133 However, these cells are rare and transcriptomic analysis of lung cancers and peritumoral tissues from mice demonstrate that the majority of infiltrating myeloid cells are actually CD11b + DCs. 135 Recently in mice, Figure 3. 130,131 The importance of DCs in lung cancer is demonstrated by ongoing efforts to harness these cells for therapeutic purposes.…”

“…134 In a more recent phase I trial, NSCLC patients receiving autologous genetically modified DCs (overexpressing lymphoid-tissue organizing chemokine CCL21) had better anti-tumour immunity, CD8 T-cell infiltration and increased tumour PD-L1 expression. 135 Recently in mice, Figure 3. Dendritic cells (DCs) are professional antigen-presenting cells that sample and present antigen to T cells within the lamina propria and associated lymph nodes.…”

Dendritic Cells and Immunogenic Cancer Cell Death: A Combination for Improving Antitumor Immunity

“…Recent clinical trials showed the efficacy of in situ DC vaccination in achieving clinical and immunological responses. In a clinical study, where CCL21 transduced DCs were used in non-small cell lung carcinomas, a significant increase in CD8+ T cell infiltration was detected in 56% of patients and it was associated with PD-L1 up-regulation [65]. Moreover, intratumoral injection of activated DCs in patients with different neoplasms enhanced lymphocyte infiltration and specific cytokine production by DCs, which correlated with stable disease and prolonged survival [66].…”