Abstract

Recent successes in immuno-oncology have focused primarily on the T-cell synapse, targeting co-activatory /inhibitory pathways to modulate T cell function. However, strategies that target tumour-resident myeloid cells may be required to fully exploit the therapeutic potential of the anti-cancer immune response. TOLL-like receptors (TLRs) are expressed on a broad range of myeloid cells and function to recognise highly evolutionarily conserved pathogen-associated molecular patterns. Signalling through TLRs leads to the activation of antigen-presenting cells (APCs) and to expression of inflammatory cytokines. However, whilst topical application of TLR agonists have proved successful in the treatment of dermatological tumours, systemic administration has proved to be poorly tolerated. MEDI9197 (formerly 3M-052), is a novel lipophilic TLR7/8 agonist designed with a lipid tail to facilitate retention at the site of injection, limiting systemic exposure. We demonstrate preclinical data to support how MEDI9197 can modulate both myeloid and lymphoid immune compartments to mediate anti-tumour activity as well as describing PD effects in patients dosed intratumorally with MEDI9197 that are consistent with its proposed mechanism of action. MEDI9197 is currently being evaluated as a monotherapy for safety and efficacy in human clinical trials (NCT02556463).