Overcoming PD-1 Blockade Resistance with CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients with Metastatic Melanoma.
Antoni RibasTheresa MedinaJoanne M JeterYousef ZakhariaRene GonzalezDiwakar DavarBartosz ChmielowskiKatie M CampbellRiyue BaoHeather KelleyAaron MorrisDavid MauroJames E WooldridgeJason J LukeGeorge J WeinerArthur M KriegMohammed M MilhemPublished in: Cancer discovery (2021)
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. SIGNIFICANCE: 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.
Keyphrases
- toll like receptor
- immune response
- nuclear factor
- inflammatory response
- dendritic cells
- advanced non small cell lung cancer
- dna methylation
- poor prognosis
- multiple sclerosis
- genome wide
- randomized controlled trial
- stem cells
- type diabetes
- high dose
- metabolic syndrome
- adipose tissue
- clinical trial
- long non coding rna
- tyrosine kinase
- combination therapy
- binding protein