Overcoming lung cancer immunotherapy resistance by combining nontoxic variants of IL-12 and IL-2
Name
172728.2-20231009104250-covered-e0fd13ba177f913fd3156f593ead4cfd.pdf
Description
Published version
Size
1.23 MB
Format
Adobe PDF
Checksum (MD5)
afb45f7a130b53ed0065a21c8f3674a8
Author(s)
Horton, Brendan L
D’Souza, Alicia D
Zagorulya, Maria
McCreery, Chloe V
Abhiraman, Gita C
Picton, Lora
Sheen, Allison
Agarwal, Yash
Momin, Noor
Wittrup, K Dane
Date Issued
September 5, 2023
Journal
JCI Insight
Publisher
American Society for Clinical Investigation
Citation
Horton, Brendan L, D’Souza, Alicia D, Zagorulya, Maria, McCreery, Chloe V, Abhiraman, Gita C et al. 2023. "Overcoming lung cancer immunotherapy resistance by combining nontoxic variants of IL-12 and IL-2." JCI Insight, 8 (19).
Version
Final published version
Abstract
Engineered cytokine-based approaches for immunotherapy of cancer are poised to enter the clinic, with IL-12 being at the forefront. However, little is known about potential mechanisms of resistance to cytokine therapies. We found that orthotopic murine lung tumors were resistant to systemically delivered IL-12 fused to murine serum albumin (MSA, IL12-MSA) because of low IL-12 receptor (IL-12R) expression on tumor-reactive CD8+ T cells. IL2-MSA increased binding of IL12-MSA by tumor-reactive CD8+ T cells, and combined administration of IL12-MSA and IL2-MSA led to enhanced tumor-reactive CD8+ T cell effector differentiation, decreased numbers of tumor-infiltrating CD4+ regulatory T cells, and increased survival of lung tumor-bearing mice. Predictably, the combination of IL-2 and IL-12 at therapeutic doses led to significant dose-limiting toxicity. Administering IL-12 and IL-2 analogs with preferential binding to cells expressing Il12rb1 and CD25, respectively, led to a significant extension of survival in mice with lung tumors while abrogating dose-limiting toxicity. These findings suggest that IL-12 and IL-2 represent a rational approach to combination cytokine therapy whose dose-limiting toxicity can be overcome with engineered cytokine variants.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
Harvard-MIT Program in Health Sciences and Technology
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Chemical Engineering
Terms of Use
Creative Commons Attribution
Persistent DSpace Link
DOI of Published Version
10.1172/jci.insight.172728
