Intratumoral expression of IL-12 from lentiviral or RNA vectors acts synergistically with TLR4 agonist (GLA) to generate anti-tumor immunological memory.

Abstract

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.

• Authors: Jardin A Leleux, Tina C Albershardt, Rebecca Reeves, Reice James, Jordan Krull, Andrea J Parsons, Jan Ter Meulen, Peter Berglund
• Journal: PloS one (PLoS One) Vol. 16 Issue 12 Pg. e0259301 ( 2021) ISSN: 1932-6203 [Electronic] United States
• PMID: 34855754 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Glucosides
• Lipid A
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• glucopyranosyl lipid-A
• Interleukin-12
• Interferon-gamma

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology)
• Female
• Gene Expression Regulation
• Genetic Vectors (administration & dosage, pharmacology)
• Glucosides (pharmacology)
• Immunity, Innate (drug effects, genetics)
• Immunologic Memory (drug effects, genetics)
• Immunotherapy (methods)
• Interferon-gamma (blood)
• Interleukin-12 (blood, genetics, immunology)
• Lentivirus (genetics)
• Lipid A (pharmacology)
• Melanoma, Experimental (genetics, immunology, therapy)
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Transgenic
• Neoplasms, Experimental (genetics, immunology, pathology)
• Toll-Like Receptor 4 (agonists)