Intratumoral Electroporation of Plasmid Encoded IL12 and Membrane-Anchored Anti-CD3 Increases Systemic Tumor Immunity

• Published in: Molecular cancer research 2022-06, Vol.20 (6), p.983-995
• Main Authors: Han, Mia, Nguyen, Bianca, Lee, Jack Y, Browning, Erica, Zhang, Jun, Mukhopadhyay, Anandaroop, Gujar, Ravindra, Salazar, Jon, Hermiz, Reneta, Svenson, Lauren, Rolig, Annah S, Redmond, William L, Algazi, Alain P, Daud, Adil I, Canton, David A, Twitty, Christopher G
• Format: Article
• Language: English
• Subjects: Electroporation; Humans; Immunotherapy; Interleukin-12 - genetics; Interleukin-12 - metabolism; Melanoma - pathology; Plasmids - genetics; Tumor Microenvironment
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-21-0834

Intratumoral delivery of plasmid IL12 via electroporation (IT-tavo-EP) induces localized expression of IL12 leading to regression of treated and distant tumors with durable responses and minimal toxicity. A key driver in amplifying this local therapy into a systemic response is the magnitude and composition of immune infiltrate in the treated tumor. While intratumoral IL12 typically increases the density of CD3+ tumor-infiltrating lymphocytes (TIL), this infiltrate is composed of a broad range of T-cell subsets, including activated tumor-specific T cells, less functional bystander T cells, as well as suppressive T regulatory cells. To encourage a more favorable on-treatment tumor microenvironment (TME), we explored combining this IL12 therapy with an intratumoral polyclonal T-cell stimulator membrane-anchored anti-CD3 to productively engage a diverse subset of lymphocytes including the nonreactive and suppressive T cells. This study highlighted that combined intratumoral electroporation of IL12 and membrane-anchored anti-CD3 plasmids can enhance cytokine production, T-cell cytotoxicity, and proliferation while limiting the suppressive capacity within the TME. These collective antitumor effects not only improve regression of treated tumors but drive systemic immunity with control of nontreated contralateral tumors in vivo. Moreover, combination of IL12 and anti-CD3 restored the function of TIL isolated from a patient with melanoma actively progressing on programmed cell death protein 1 (PD-1) checkpoint inhibitor therapy. This DNA-encodable polyclonal T-cell stimulator (membrane-anchored anti-CD3 plasmid) may represent a key addition to intratumoral IL12 therapies in the clinic.