Abstract P046: CTLA4 targeted therapy using the lymphatic drug delivery system for treatment of metastatic lymph nodes

Background: Metastasis is the prime cause of cancer associated mortality. Lymph nodes (LNs) facilitate the systemic exposure of tumor cells, resulting in fatal systemic metastasis. Treatment of metastatic LNs is therefore imperative. However, successful treatment of metastatic LNs is challenging. Immune checkpoint inhibitor (ICI) therapy is an emerging therapy approved for several advanced malignancies. However, ICI therapy in the context of metastatic LNs remains unexplored due to the absence of reliable models and inquisition techniques. Additionally, while systemically delivered ICI therapy has delivered encouraging results, response is often erratic and mired by unwarranted side effects. To harness the benefits of ICI therapy, it is imperative to uncouple therapeutic response from off-target events. The present study sought to develop an effective intervention strategy using α-CTLA4 mAb for the treatment of metastatic LNs that addresses this unmet need. Methods: Using a murine model of LN metastasis, the therapeutic efficacy of low-dose α-CTLA4 mAb administered to different sites locally, using a novel lymphatic drug delivery system (LDDS) or intraperitoneally (i.p.) was examined. The mouse model was established using luciferase labelled cells in a recombinant inbred strain of mice exhibiting systemic lymphadenopathy (LM8-Luc cells; MXH10/Mo/lpr mice). Results: Therapeutic response was observed in mice treated by all strategies with α-CTLA4 mAb. However, response was erratic in mice administered α-CTLA4 mAb to tumor-free LN through LDDS or intraperitoneally. Strong and fairly consistent therapeutic response was observed upon local delivery of α-CTLA4 mAb through LDDS to tumor-harboring LN. Additionally, incidence of complete response, as indicated by the total-eradication of tumor by the pre-determined experimental endpoint was observed in 66.67% of mice treated by the administration of α-CTLA4 mAb to tumor-harboring LN as opposed to only 33.33% and 28.67% in mice treated by administration of α-CTLA4 mAb to the tumor-free LN or intraperitoneally. Furthermore, treatment using LDDS to tumor-bearing LN was also found to prevent metastases to liver and lung and significantly prolong survival. In stark contrast, treatment through LDDS to tumor-free LN or i.p., worsened survival as opposed to control group, likely due to the onset of immune related adverse events. In keeping with the same, body weight and spleen weights for the i.p. group, which had the wors