Dendritic cell vaccine-based immunotherapy in combination with salvage chemotherapy for patients with advanced or relapsed gastric cancer

Abstract

Introduction: Gastric cancer is one of the most lethal cancers despite many advances in therapy. Recently, immune checkpoint blockade agents have been demonstrated to be effective for patients with gastric cancer in advanced stage. However, the efficacy is in the range of 10-30%. New therapeutic modalities are needed for patients with refractory disease. We conducted a phase I/II clinical trial of dendritic cell (DC) vaccination for patients with advanced or relapsed gastric cancer in combination with salvage chemotherapies. Methods: Twenty patients (14 males, 6 females; aged 24-88 years) were enrolled in the present study. Autologous DCs were generated using a standard protocol. Wilms' tumor 1 (WT1) and/or mucin 1 (MUC1) peptide-loaded mature DCs and OK432, a toll-like receptor 4 agonist, were administered intradermally every 2 weeks, 7 times in combination with salvage chemotherapies. Induction of vaccine-induced T cell responses was evaluated by an enzyme-linked immunospot (ELISPOT) or CD107a mobilization assay. Primary endpoints were safety and disease control rate. Secondary endpoints were overall survival (OS) and peptide-specific T cell responses. This study was registered in University Hospital Medical Information Network (UMIN) in Japan (UMIN 000027279). Results: The treatment was well tolerated and none of the patients experienced more than grade 2 adverse events except for hematological toxicities. Two had partial response (PR), 7 had stable disease (SD) and 11 had disease progression (PD) following DC vaccination. Median OS from the date of the first vaccination was 10.5 months with the median observation period of 10.3 months. OS of patients achieving PR or SD after DC vaccination (responder) was significantly longer than those who did not respond to the treatment (non-responder) (median OS; 26.3 vs 6.4 months, p<0.001). ELISPOT assays showed a marked increase in mean number of WT1 or MUC1-specific spots in responders in comparison with non-responders following DC vaccination; 41.4 and 7.0 fold in responders and non-responders, respectively. Similarly, CD107a mobilization assays demonstrated significant increase in responders following vaccination, suggesting that tumor specific immunity augmented by DC vaccination might result in the stabilization of disease and the prolongation of survival. There was a trend toward moderate increase in the percentage of NK cells, NKT cells and GdT cells following vaccination in responders. The percentage of regulatory T cells (Treg) and myeloidderived suppressor cells (MDSC) decreased by 22% and 41%, respectively in responders. On the other hand, both the percentage of Treg and MDSC increased by 25% and 32%, respectively in non-responders, indicating that DC vaccination may contribute to the reversal of immunosuppression by these cells. Conclusion: DC vaccine-based immunotherapy combined with a salvage chemotherapy was demonstrated to be safe and elicit both innate and acquired cellular immune responses which might be correlated to clinical outcome.