A TLR7 agonist enhances the antitumor efficacy of obinutuzumab in murine lymphoma models via NK cells and CD4 T cells

Abstract

Anti-CD20 monoclonal antibodies (mAb) such as rituximab have been proven to be 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-CLL. We hypothesized that immune stimulation through Toll-like receptor 7 (TLR7) agonism in combination with obinutuzumab would further enhance lymphoma clearance and the generation of long-term antitumor immune responses. Here we demonstrate, in syngeneic human CD20 (hCD20)-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 antitumor activity is dependent on both NK cells and CD4+ T cells but not on 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 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.

Toll-Like Receptors in Natural Killer Cells and Their Application for Immunotherapy

“…In syngeneic human CD20-(hCD20-) expressing models of lymphoma, systemic administration of a TLR7 agonist (R848) reportedly augmented responses upon combinatorial administration with obinutuzumab, thus preventing tumor recurrence. Furthermore, primary antitumor activity depended on both NK cells and CD4 + T cells but not on CD8 + T cells, suggesting that combinatorial treatment with TLR7 agonists potentially improves the outcome of obinutuzumab treatment [86].…”

The Role of Toll-Like Receptor in Inflammation and Tumor Immunity

“…TLRs have attracted a substantial of interest in cancer research due to the clinical relevance of TLRs expression and tumor control ( Pradere et al, 2014 ). Accumulated evidences indicate that artificial activation of TLRs on the immune cells, including monocytes, macrophages, and dendritic cells (DCs), can generate strong efficacy to boost therapy-elicited anticancer immunity, characterized by priming CD8+ T-cell and natural killer cells (NK cells) ( Mogensen, 2009 ; Cheadle et al, 2017 ).…”

Therapeutic ISCOMATRIX™ adjuvant vaccine elicits effective anti-tumor immunity in the TRAMP-C1 mouse model of prostate cancer

“…This does not exclude that memory CD4 + T cells are also recalled or the possibility that NK cells are again activated following rechallenge. A study by Cheadle et al [46] investigating the potential of TLR7 agonism in improving anti-tumor efficacy of Obinutuzumab (glygoengineered α-CD20) in murine lymphoma models demonstrated that primary anti-tumor immunity was dependent on both NK cells an CD4 + T cells but not CD8 + T cells. The improved response observed is thought to reflect the ability of R848 to potentiate Obinutuzumab's effector mechanism, in particular Ab-dependent cell-mediated cytotoxicity by NK cells.…”