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.
Author Info: (1) University of California, San Francisco, San Francisco, California. (2) OncoSec Medical Incorporated, Pennington, New Jersey. (3) University of California, San Francisco, San F
Author Info: (1) University of California, San Francisco, San Francisco, California. (2) OncoSec Medical Incorporated, Pennington, New Jersey. (3) University of California, San Francisco, San Francisco, California. (4) DR HOPE LLC, Seattle, Washington. (5) Fred Hutchinson Cancer Research Center, Seattle, Washington. (6) OncoSec Medical Incorporated, Pennington, New Jersey. (7) OncoSec Medical Incorporated, Pennington, New Jersey. (8) OncoSec Medical Incorporated, Pennington, New Jersey. (9) OncoSec Medical Incorporated, Pennington, New Jersey. (10) University of California, San Francisco, San Francisco, California. (11) OncoSec Medical Incorporated, Pennington, New Jersey. (12) University of California, San Francisco, San Francisco, California. (13) Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. (14) Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania. (15) Rockefeller University, New York, New York. (16) University of California, San Francisco, San Francisco, California. (17) Earle A. Chiles Research Institute, Portland, Oregon. (18) Earle A. Chiles Research Institute, Portland, Oregon. (19) Fred Hutchinson Cancer Research Center, Seattle, Washington. (20) OncoSec Medical Incorporated, Pennington, New Jersey. (21) Huntsman Cancer Institute, Salt Lake City, Utah. (22) Earle A. Chiles Research Institute, Portland, Oregon. (23) University of California, San Francisco, San Francisco, California. (24) University of California, San Francisco, San Francisco, California. Adil.daud@ucsf.edu.
