Abstract CT134: Intratumoral electroporation of plasmid IL-12 can prime response to anti-PD1/PD-L1 blockade in patients with Stage III/IV-M1a melanoma

Abstract

Background: Intratumoral electroporation of plasmid IL-12 (IT-pIL12-EP) induces tumor infiltrating lymphocytes (TILs) and anti-tumor immunity in melanoma as described in previous Phase 1 and 2 clinical trials. PD-1 and PD-L1 antibodies induce durable tumor responses in advanced melanoma, however responses to these agents are far less common in tumors lacking significant numbers of TILs. Therefore, in this retrospective study, patients were evaluated for response to anti-PD-1/PD-L1 therapies post IT-pIL12-EP. Methods: A multi-center, Phase 2 trial of IT-pIL12-EP was conducted in patients with stage III/IV melanoma. Upon disease progression or treatment discontinuation with IT-pIL12-EP, many patients received subsequent PD-1/PD-L1 inhibitors. Patients with documented follow up history and evaluable for anti-PD-1/PD-L1 response were included in this analysis. Results: We evaluated 34 patients enrolled and treated with IT-pIL12-EP monotherapy at a single center, of which, 14 patients went on to receive a systemic PD-1/PD-L1 inhibitor and were evaluable for PD-1/PD-L1 best overall response (BOR). The PD-1/PD-L1-associated BOR was 9/14 (64%) with CR in 5 patients (36%), PR in 4 (29%), SD in 2 (14%), and PD in 3 (21%). Eight of these evaluable patients received a systemic PD-1/PD-L1 inhibitor with no intervening therapy post-IT-pIL12-EP. Of these 8 patients, a BOR of 75% was observed (50% CR and 25% PR). Conclusion: Patients who received IT-pIL12-EP and later went on to receive a PD-1/PD-L1 inhibitor demonstrated a high PD-1/PD-L1-associated response rate (64% CR+PR). Interestingly, patients who received a PD-1/PD-L1 inhibitor with no intervening therapy post-IT-pIL12-EP had a BOR of 75% (CR+PR). These data suggest that IT-pIL12-EP may prime for responses to PD-1 blockade. Patient tumor samples are being evaluated for TIL status and gene expression analysis to determine the mechanism of IT-pIL12-EP priming. A prospective clinical trial combining IT-pIL12-EP and pembrolizumab in advanced melanoma is ongoing at the University of California San Francisco. NCT01502293 Citation Format: Alain Algazi, Katy K. Tsai, Kathryn T. Takamura, Lawrence Chen, Chris Twitty, Mary Dwyer, Samantha Greaney, Tu Diep, Robert H. Pierce, Mai H. Le, Lawrence Fong, Adil Daud. Intratumoral electroporation of plasmid IL-12 can prime response to anti-PD1/PD-L1 blockade in patients with Stage III/IV-M1a melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT134.

Relaxin-expressing oncolytic adenovirus induces remodeling of physical and immunological aspects of cold tumor to potentiate PD-1 blockade

“… 46 In line with our findings, a phase II clinical trial, which combines IL-12-expressing plasmid DNA and αPD-1 Ab, demonstrated that IL-12 expression enhances the response to αPD-1 therapy in patients with low levels of TILs. 47 Because viral vectors, especially Ad, often express therapeutic genes at a much higher level than plasmid vectors (the difference is further magnified when oncolytic vectors are compared due to the exponential amplification in therapeutic gene expression following viral replication), immune stimulatory oncolytic viral vectors in combination with ICIs may yield promising results against cold tumors in future clinical trials.…”

Cytokines as potential combination agents with PD‐1/PD‐L1 blockade for cancer treatment

“…Moreover, a Phase II clinical trial was conducted to test the antitumor activity of electroporation of plasmid IL‐12 combining with pembrolizumab in patients ( n = 34) with advanced melanoma (Stage III/IV). Preliminary clinical data was demonstrated that IL‐12 may prime for responses to PD‐1 inhibitor (NCT01502293; Algazi et al, 2016). It is clear from the results of these studies that IL‐12 has a potential effect against malignancies, especially when used at optimal dose and schedule of administration to prevent its probably side effector or utilized in combination with immune checkpoint inhibition can enhance the host immune response.…”

Melanoma Treatment with Intratumoral Electroporation of Tavokinogene Telseplasmid (pIL-12, Tavokinogene Telseplasmid)

“…Intratumoral injection of plasmid IL-12 pUMVC3-hIL-12-NGVL3 followed by electroporation (IT-tavo-EP) results in highly localized IL-12 expression and very-low systemic doses of Clinical data to date demonstrate that IT-tavo-EP acts as an in situ tumor vaccine by inducing local IL-12 expression which, in turn, leads to intratumoral inflammation and tumor antigen presentation, recruitment of T cells, enhanced Th1 immune responses, and, importantly, systemic immune response with minimal systemic toxicity [13,56,57]. These systemic, biological effects of IT-tavo-EP could be synergistic with the activities of PD-1 and PD-L1 antibodies, and clinical trials are ongoing to formally evaluate this potential synergy.…”