Abstract
SummaryMonoclonal antibodies (mAbs) can destroy tumors by recruiting effectors such as myeloid cells, or targeting immunomodulatory receptors to promote cytotoxic T cell responses. Here, we examined the therapeutic potential of combining a direct tumor-targeting mAb, anti-CD20, with an extended panel of immunomodulatory mAbs. Only the anti-CD27/CD20 combination provided cures. This was apparent in multiple lymphoma models, including huCD27 transgenic mice using the anti-huCD27, varlilumab. Detailed mechanistic analysis using single-cell RNA sequencing demonstrated that anti-CD27 stimulated CD8+ T and natural killer cells to release myeloid chemo-attractants and interferon gamma, to elicit myeloid infiltration and macrophage activation. This study demonstrates the therapeutic advantage of using an immunomodulatory mAb to regulate lymphoid cells, which then recruit and activate myeloid cells for enhanced killing of mAb-opsonized tumors.
Highlights
Monoclonal antibodies have proven to be potent tools in cancer treatment. They can be divided into two groups based on their effector functions: direct tumortargeting mAbs, such as anti-CD20, anti-Her2, and anti-EGFR target the tumor directly through innate effectors, whereas immunomodulatory mAbs activate the adaptive immune system
It has previously been shown that, when combined, certain immunomodulatory mAbs (e.g., 4-1BB) can improve the anti-tumor efficacy of direct tumor-targeting mAbs (CD20) (Souza-Fonseca-Guimaraes et al, 2016) through enhancement of natural killer (NK) cell-mediated antibodydependent cellular cytotoxicity (ADCC) (Gill et al, 2012; Kohrt et al, 2011), which has moved to the clinical setting for validation
We examined whether the anti-tumor efficacy of the archetypal direct-targeting mAb, anti-CD20, could be enhanced by different immunomodulatory mAbs
Summary
Monoclonal antibodies (mAbs) have proven to be potent tools in cancer treatment (reviewed in Weiner, 2015) They can be divided into two groups based on their effector functions: direct tumortargeting mAbs, such as anti-CD20, anti-Her, and anti-EGFR target the tumor directly through innate effectors, whereas immunomodulatory mAbs (e.g., anti-PD-1, anti-PD-L1, anti-CTLA-4, and anti-CD40) activate the adaptive immune system. It has previously been shown that, when combined, certain immunomodulatory mAbs (e.g., 4-1BB) can improve the anti-tumor efficacy of direct tumor-targeting mAbs (CD20) (Souza-Fonseca-Guimaraes et al, 2016) through enhancement of natural killer (NK) cell-mediated antibodydependent cellular cytotoxicity (ADCC) (Gill et al, 2012; Kohrt et al, 2011), which has moved to the clinical setting for validation. We examined whether the anti-tumor efficacy of the archetypal direct-targeting mAb, anti-CD20, could be enhanced by different immunomodulatory mAbs
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