Algazi et al. investigated the combination of intratumoral plasmid IL-12 tavokinogene telseplasmid (i.t. tavo) and pembrolizumab in advanced melanoma patients with cold tumors (<25% checkpoint-positive CTLs) who were unlikely to respond to, or had previously failed, anti-PD-1 monotherapy. 23 eligible patients were treated with i.t. tavo/pembrolizumab for up to 2 years, which was well-tolerated. The ORR was 41%, with 36% CR. CD8+ TIL, unique TCRβ sequences, PD-L1, and Agn presentation genes, as well as Temra cells in PB were significantly increased. Treatment-related effects were seen in both i.t. tavo-injected and non-injected tumors.
Contributed by Katherine Turner
PURPOSE: Tumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL). PATIENTS AND METHODS: Tavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done. RESULTS: The combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNgamma feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses. CONCLUSIONS: The combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors.