PD-L1 expression correlates with immune response in a Phase I trial of CCL21 gene modified dendritic cell therapy in lung cancer
© Lee et al.; licensee BioMed Central Ltd. 2014
Published: 6 November 2014
Anti-tumor immune response in lung cancer patients may be evoked by intra-tumoral (IT) administration of autologous dendritic cells (DC), transduced with a replication-deficient adenoviral (Ad) vector to express the secondary lymphoid chemokine (SLC/CCL21) gene. Here, we evaluated tumor specific immune response after CCL21 gene-modified DC (Ad-CCL21-DC) administration in the context of tumor PD-L1 expression.
Phase I, non-randomized, dose escalating, multi-cohort trial was conducted to enroll patients with Stage IIIB/IV NSCLC. Sixteen patients received 2 vaccinations at a dose of Ad-CCL21-DC (A, B, C, or D; 1 × 106, 5 × 106, 1 × 107, or 3 × 107 cells/injection) by IT injection (days 0 and 7). Peripheral blood was collected for antigen-specific ELISPOT assays, and CT guided needle biopsies of the primary lung cancer were obtained for PD-L1 expression by real time PCR and evaluation of cellular infiltrates by immunohistochemistry.
Peripheral blood of 16 subjects was evaluated by ELISPOT assays. Positive response was defined as 2-fold increase in number of spots above background with an absolute number of >20 spots/2 × 105 cells (positive responder; PR). A mixed response was defined as a positive response with high IFN-γ background expression at day 0 compared to post-vaccine time points (mixed responder; MR). There were 19% (3/16) PR and 19% (3/16) MR for a total of 38% (6/16) total responders. The average PD-L1 gene copy number was 1344 (non-responder; NR) compared to 394 (MR), and 684 (PR) on day 7. Tumor CD8 T cell infiltration was induced in 40% (6/15; all subjects), 33% (3/9; NR), and 50% (3/6; MR & PR).
Intra-tumoral administration of autologous dendritic cells expressing the SLC/CCL21 gene demonstrated that 1) anti-tumor specific immune responses are elicited and correlate with lower PD-L1 expression, and 2) CD8 T cell infiltration into the tumor is induced.
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