Intratumoral vidutolimod (CpG-A TLR9 agonist) together with pembrolizumab overcomes PD-1 blockade resistance in 25% of patients with metastatic melanoma with manageable toxicities in a phase I trial.,Patients with advanced melanoma that is resistant to PD-1 blockade therapy have limited treatment options.,Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong IFN response to induce and attract antitumor T cells.,In the dose-escalation part of this phase Ib study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti-PD-1 therapy.,The combination of vidutolimod and pembrolizumab had a manageable safety profile, and durable responses were observed in 25% of patients, with tumor regression in both injected and noninjected lesions, including visceral lesions.,Patients who responded to vidutolimod and pembrolizumab had noninflamed tumors at baseline and induction of an IFNγ gene signature following treatment, as well as increased systemic expression of the IFN-inducible chemokine CXCL10.,In this phase Ib study in patients with advanced melanoma, intratumoral TLR9 agonist vidutolimod in combination with pembrolizumab had a manageable safety profile and showed promising clinical activity, supporting the further clinical development of vidutolimod to overcome PD-1 blockade resistance through induction of an IFN response.,See related commentary by Sullivan, p.,2960.,This article is highlighted in the In This Issue feature, p.,2945
The emergence of human intratumoural immunotherapy (HIT-IT) is a major step forward in the management of unresectable melanoma.,The direct injection of treatments into melanoma lesions can cause cell lysis and induce a local immune response, and might be associated with a systemic immune response.,Directly injecting immunotherapies into tumours achieves a high local concentration of immunostimulatory agent while minimising systemic exposure and, as such, HIT-IT agents are associated with lower toxicity than systemic immune checkpoint inhibitors (CPIs), enabling their potential use in combination with other therapies.,Consequently, multiple HIT-IT agents, including oncolytic viruses, pattern-recognition receptor agonists, injected CPIs, cytokines and immune glycolipids, are under investigation.,This review considers the current clinical development status of HIT-IT agents as monotherapy and in combination with systemic CPIs, and the practical aspects of administering and assessing the response to these agents.,The future of HIT-IT probably lies in its use in combination with systemic CPIs; data from Phase 2 trials indicate a synergy between HIT-IT and CPIs.,Data also suggest that the addition of HIT-IT to a CPI might generate responses in CPI-refractory tumours, thereby overcoming resistance and addressing a current unmet need in unresectable and metastatic melanoma for treatment options following progression after CPI treatment.