A TLR7 agonist enhances the anti-tumor efficacy of obinutuzumab in murine lymphoma models via NK cells and CD4 T cells.

Abstract

Anti-CD20 mAb such as rituximab have proven highly effective at improving outcome in B-cell malignancies. However, many patients ultimately relapse and become refractory to treatment. The glycoengineered anti-CD20 mAb obinutuzumab was developed to induce enhanced antibody dependent cellular cytotoxicity, antibody dependent phagocytosis and direct cell death and was shown to lead to improved outcomes in a randomized study in B-chronic lymphocytic leukemia (B-CLL). We hypothesized that immune stimulation through TLR7 agonism in combination with obinutuzumab would further enhance lymphoma clearance and the generation of long-term anti-tumor immune responses. Here we demonstrate in syngeneic human CD20-expressing models of lymphoma that systemic administration of a TLR7 agonist (R848) increases responses when administered in combination with obinutuzumab and protects against disease recurrence. Depletion studies demonstrate that primary anti-tumor activity is dependent on both NK cells and CD4(+) T-cells but not CD8(+) T-cells. However, both CD4(+) and CD8(+) T-cells appear necessary for the generation of protective immunological memory. Importantly, increased tumor-free survival post obinutuzumab and R848 combination therapy was seen in human CD20 (hCD20) transgenic mice which express hCD20 on normal B-cells. These findings provide a rationale for clinical testing of obinutuzumab in combination with systemically administered TLR7 agonists to further improve outcome.Leukemia accepted article preview online, 28 November 2016. doi:10.1038/leu.2016.352.