Abstract

Background

Tumour-targeting monoclonal antibodies (mAb) such as anti-CD20 exert their anti-tumour activity through macrophage-mediated antibody-dependent cellular phagocytosis (ADCP).  We examined whether the efficacy of CD20 mAb could be augmented by combination with immunomodulatory mAbs against PD-1, CTLA-4, OX40, GITR, and CD27.  CD27 is a TNFR superfamily member expressed constitutively on T and NK cells and has been shown to regulate CD8⁺ T-cell priming, cytotoxicity, and memory responses.

Method

mAb combinations were tested in multiple immunocompetent murine B-cell lymphoma models (BCL1, A31 and Em-TCL1) and in human CD27 transgenic mice.  We dissected the mechanism of action of the mAbs through single-cell RNA sequencing and functional immunological assays.

Results

Amongst the immunomodulatory mAb tested with anti-CD20, only addition of an agonistic mAb against CD27 markedly improved the survival of BCL1 lymphoma-bearing mice.  Similar results were observed in multiple B-cell lymphoma models.

Profound myeloid cell infiltration and activation was observed in mice treated with anti-CD27.  mRNA expression of known myeloid chemoattractants (CCL3, CCL4 and CCL5) and IFNg was observed on CD8⁺ T cells.  In vivo neutralisation of IFNg or depletion of T and NK cells, abrogated myeloid cell infiltration by anti-CD27.  Further, macrophages from anti-CD27 treated mice demonstrated increased phagocytic ability in the presence of anti-CD20.

Conclusion

These data demonstrate the therapeutic potential of combining a tumour-targeting mAb with an immunostimulating mAb, through a hitherto, unexpected mechanism of action involving activation of the innate immunity.  Here, anti-CD27 indirectly increased the capacity of macrophages to perform anti-CD20-mediated ADCP through T-cell activation. Based upon these data, a U.K. multicentre phase II clinical trial examining rituximab and varlilumab (anti-CD27) in relapsed and/or refractory B-cell lymphoma has been initiated (RIVA trial NCT03307746).