Clinical efficacy of anti-PD-1 immunotherapy with localized non-ablative irradiation against metastatic lymph node in patients with metastatic gastric cancer

Abstract Background Cancer immunotherapy combining radiotherapy and anti-PD-1 therapy is a promising treatment strategy. However, the optimal method of radiotherapy to combine with anti-PD-1 therapy has not yet been established. We investigated the clinical efficacy of combinatorial immunotherapy with nivolumab and localized non-ablative irradiation against metastatic lymph node (Nivo-lRT_mLN) in patients with metastatic gastric cancer (m-GC). Materials and Methods This exploratory study included 16 patients with m-GC and nivolumab was administered after non-ablative irradiation, 22.5 Gy/5fractions, on one metastatic lymph node measuring 2.0 cm or larger. We evaluated the immunological characteristics associated with the therapeutic efficacy of Nivo-lRT_mLN by multiplex analysis of cytokines, T cell receptor repertoire and flow cytometric analysis using peripheral blood samples. Results More than 80% (13 out of 16) of patients had more than 5 metastases and 75% (12 out of 16) of patients had metastases in more than 2 organs. Rate of complete response (CR), partial response (PR), and stable disease (SD) in Nivo-lRT_mLN were 18.7%, 18.7%, and 25.0%. Median survival time was 10.3 months and 4 patients survived for more than five years without recurrence. Before treatment, IL-1ra level was significantly lower and frequency of CD8(+)CD45RO(+)CD27(+)CD127(+) T cells was significantly higher in non-progressors (CR/PR/SD) compared to progressors (PD/NE) and the high group with frequency of CD8(+)CD45RO(+)CD27(+)CD127(+) T cells had significantly better overall survival (OS) than the low group (p = 0.0081). The time-dependent ROC AUC at both the level of IL-1ra and frequency of CD8(+)CD45RO(+)CD27(+)CD127(+) T cells significantly predict OS (p = 0.0193 and p = 0.0442). Conclusions These preliminary findings indicated that localized non-ablative irradiation against metastatic lymph node has a potential to enhance the clinical efficacy of anti-PD-1 immunotherapy in patients with m-GC, and IL-1ra level and frequency of CD8(+)CD45RO(+)CD27(+)CD127(+) T cells in peripheral blood before treatment may be candidate biomarkers to predict clinical efficacy of Nivo-lRT_mLN.