Intratumoral expression of IL-12 from lentiviral or RNA vectors acts synergistically with TLR4 agonist

• Published in: PloS one Vol. 16; no. 12; p. e0259301
• Main Authors: Leleux, Jardin A, Albershardt, Tina C, Reeves, Rebecca, James, Reice, Krull, Jordan, Parsons, Andrea J, ter Meulen, Jan, Berglund, Peter
• Format: Journal Article
• Language: English
• Published: Public Library of Science 02-12-2021
• Subjects: Analysis; Complications and side effects; Diagnosis; Gene therapy; Interleukin-12; Patient outcomes; Tumors; United States
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0259301

Systemic interleukin-12 (IL12) anti-tumor therapy is highly potent but has had limited utility in the clinic due to severe toxicity. Here, we present two IL12-expressing vector platforms, both of which can overcome the deficiencies of previous systemic IL12 therapies: 1) an integrating lentiviral vector, and 2) a self-replicating messenger RNA formulated with polyethyleneimine. Intratumoral administration of either IL12 vector platform resulted in recruitment of immune cells, including effector T cells and dendritic cells, and the complete remission of established tumors in multiple murine models. Furthermore, concurrent intratumoral administration of the synthetic TLR4 agonist glucopyranosyl lipid A formulated in a stable emulsion (GLA-SE) induced systemic memory T cell responses that mediated complete protection against tumor rechallenge in all survivor mice (8/8 rechallenged mice), whereas only 2/6 total rechallenged mice treated with intratrumoral IL12 monotherapy rejected the rechallenge. Taken together, expression of vectorized IL12 in combination with a TLR4 agonist represents a varied approach to broaden the applicability of intratumoral immune therapies of solid tumors.