Focusing on resistance mechanisms to cytokine therapies, Horton et al. found that systemic mouse serum albumin (MSA)-fused IL-12 therapy in a lung tumor model failed to control lung tumor growth due to low IL-12R levels on tumor-reactive T cells in the lung, while successfully controlling growth of flank tumors. Addition of MSA-IL-2 increased IL-12 binding to tumor-reactive T cells, and the combination increased tumor-reactive CD8+ T cell effector differentiation, decreased Tregs, and increased survival, but was associated with significant dose-limiting toxicity. Toxicity was alleviated using a combination of engineered IL-2 and IL-12 variants shown to have reduced dose-limiting toxicity.
Contributed by Katherine Turner
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) due to low 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 (Treg) 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.
Author Info: (1) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States of America. (2) Koch Institute for Integrative Cancer Research,
Author Info: (1) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States of America. (2) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States of America. (3) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States of America. (4) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States of America. (5) Department of Structural Biology, Stanford University, Sanford, United States of America. (6) Department of Medicine, Stanford University, Sanford, United States of America. (7) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States of America. (8) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States of America. (9) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States of America. (10) Massachusetts Institute of Technology, Cambridge, United States of America. (11) Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States of America. (12) Stanford University, Sanford, United States of America. (13) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States of America.
