Immunologic changes in patients with metastatic melanoma on bevacizumab and chemotherapy versus chemotherapy alone.

Abstract

e21112 Background: Metastatic malignant melanoma is difficult to treat and has a poor prognosis. Systemic therapy for metastatic melanoma has had limited success and novel drug combinations need to be tested. To that end, we have combined anti-angiogenic therapy (bevacizumab) with chemotherapy in clinical trials and have shown some clinical efficacy. Vascular endothelial growth factor (VEGF) is increasingly seen as an immunosuppressive factor that hampers dendritic cell maturation and reduces antigen presentation. We have recently shown that tumor-derived VEGF plays a role in Th-2 driven systemic chronic inflammation seen in advanced melanoma patients. Therefore, our data suggest that blocking tumor derived VEGF with the monoclonal antibody bevacizumab may impact immunity in such a way that augments anti-tumor immunity enhancing clinical efficacy. Methods: In order to understand the immune status in metastatic melanoma patients on chemotherapy (n=55) or chemotherapy plus bevacizumab (n=73), we measured levels of 42 cytokines, chemokines and growth factors in plasma by a mulit-plex bead assay. Matched pairs analysis was performed to determine if the average responses of the measured cytokines were different between the patients that received chemotherapy with bevacizumab or chemotherapy alone. The pre-treatment levels were compared with levels drawn four weeks after the first treatment. Results: There were significant differences in IL-1a, IL-1ra, IL-6, IL-8 and IP-10 between patients treated with chemotherapy alone relative to patients treated with chemotherapy plus bevacizumab. In all cases of patients treated with chemotherapy plus bevacizumab, the levels of these cytokines all decreased relative to pre-treatment samples. In patients treated with chemotherapy alone the levels of these cytokines increased relative to pre-treatment samples. Conclusions: Our data suggest that treating patients with the anti-angiogenic drug bevacizumab may affect the plasma cytokine milieu by reducing the level of many key inflammatory cytokines. Therefore, the use of bevacizumab in combination with chemotherapy may augment host immunity and elicit a more effective anti-tumor immune response.