• Improving therapeutic activity of anti-CD20 antibody therapy through immunomodulation in lymphoid malignancies.

      Lipowska-Bhalla, Grazyna; Fagnano, Ester; Illidge, Timothy M; Cheadle, Eleanor J; Targeted Therapy Group, Institute of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre , Manchester (2016-04-06)
      Nearly two decades ago rituximab heralded a new era in management of B cell malignancies significantly increasing response rates and survival. However, despite clear therapeutic advantage, significant numbers of patients become refractory to anti-CD20 mAb therapy, suggesting urgent improvements are required. It is now well recognized that the suppressive tumor microenvironment plays an important role in the outcome of anti-CD20 mAb therapy and that manipulation of this environment may improve the efficacy and produce long-term tumor control. The past few years have seen a surge of interest in immunomodulatory agents capable of overwriting immune suppressive networks into favorable clinical outcome. Currently, a number of such combinations with anti-CD20 mAb is under evaluation and some have produced encouraging outcomes in rituximab refractory disease. In this review, we give an outline of anti-CD20 mAbs and explore the combinations with immunomodulatory agents that enhance antitumor immunity through targeting stimulatory or inhibitory pathways and have proven potential to synergize with anti-CD20 mAb therapy. These agents, primarily mAbs, target CTLA-4, PD-1/PD-L1, and CD40.
    • A TLR7 agonist enhances the anti-tumor efficacy of obinutuzumab in murine lymphoma models via NK cells and CD4 T cells.

      Cheadle, Eleanor J; Lipowska-Bhalla, Grazyna; Dovedi, Simon J; Fagnano, Ester; Klein, C; Honeychurch, Jamie; Illidge, Timothy M; Targeted Therapy Group, Division of Molecular and Clinical Cancer Sciences, University of Manchester, Christie Hospital, Manchester (2016-11-28)
      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.