Abstract
BackgroundImmune checkpoint blockade (ICB) promotes adaptive immunity and tumor regression in some cancer patients. However, in patients with immunologically “cold” tumors, tumor-resident innate immune cell activation may be required to prime an adaptive immune response and so exploit the full potential of ICB. Whilst Toll-like receptor (TLR) agonists have been used topically to successfully treat some superficial skin tumors, systemic TLR agonists have not been well-tolerated.MethodsThe response of human immune cells to TLR7 and 8 agonism was measured in primary human immune cell assays. MEDI9197 (3M-052) was designed as a novel lipophilic TLR7/8 agonist that is retained at the injection site, limiting systemic exposure. Retention of the TLR7/8 agonist at the site of injection was demonstrated using quantitative whole-body autoradiography, HPLC-UV, and MALDI mass spectrometry imaging. Pharmacodynamic changes on T cells from TLR7/8 agonist treated B16-OVA tumors was assessed by histology, quantitative real time PCR, and flow cytometry. Combination activity of TLR7/8 agonism with immunotherapies was assessed in vitro by human DC-T cell MLR assay, and in vivo using multiple syngeneic mouse tumor models.ResultsTargeting both TLR7 and 8 triggers an innate and adaptive immune response in primary human immune cells, exemplified by secretion of IFNα, IL-12 and IFNγ. In contrast, a STING or a TLR9 agonist primarily induces release of IFNα. We demonstrate that the TLR7/8 agonist, MEDI9197, is retained at the sight of injection with limited systemic exposure. This localized TLR7/8 agonism leads to Th1 polarization, enrichment and activation of natural killer (NK) and CD8+ T cells, and inhibition of tumor growth in multiple syngeneic models. The anti-tumor activity of this TLR7/8 agonist is enhanced when combined with T cell-targeted immunotherapies in pre-clinical models.ConclusionLocalized TLR7/8 agonism can enhance recruitment and activation of immune cells in tumors and polarize anti-tumor immunity towards a Th1 response. Moreover, we demonstrate that the anti-tumor effects of this TLR7/8 agonist can be enhanced through combination with checkpoint inhibitors and co-stimulatory agonists.
Highlights
Immune checkpoint blockade (ICB) monoclonal antibodies targeting inhibitory pathways at the T cell synapse to modulate T cell function have shown activity in the treatment of multiple cancers, as demonstrated by numerous regulatory approvals [1, 2]
MEDI9197 has been shown to have activity in mouse vaccine and cancer models and synergize with other immunotherapies [22,23,24]. In this manuscript we demonstrate that targeting TLR7 and 8 compared with TLR9 or stimulator of interferon genes (STING) in human PBMCs leads to induction of a broader range of cytokines
MEDI9197 induced IFNα and IL12p40 release from Plasmacytoid dendritic cells (pDC) and Myeloid dendritic cells (mDC) populations, respectively, which were enriched from human PBMCs (Fig. 1b)
Summary
ICB monoclonal antibodies (mAbs) targeting inhibitory pathways at the T cell synapse to modulate T cell function have shown activity in the treatment of multiple cancers, as demonstrated by numerous regulatory approvals [1, 2]. Patients with few TILs, so called “cold” tumors, tend to respond poorly to ICB mAbs. Therapeutic strategies that target tumor-resident innate immune cells and induce local tumor proinflammatory responses, which recruit CD8+ TILs, may be required to fully exploit the potential of ICB mAbs. One strategy to turn an immunologically cold tumor hot is to promote activation of antigen presenting cells (APC) by targeting the endosomal TLRs TLR3, TLR7, TLR8, TLR9, or by targeting the ER-associated signalling molecule stimulator of interferon genes (STING). Immune checkpoint blockade (ICB) promotes adaptive immunity and tumor regression in some cancer patients. In patients with immunologically “cold” tumors, tumor-resident innate immune cell activation may be required to prime an adaptive immune response and so exploit the full potential of ICB. Whilst Toll-like receptor (TLR) agonists have been used topically to successfully treat some superficial skin tumors, systemic TLR agonists have not been well-tolerated
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