An IL-2 proaerolysin fusion toxin that selectively eliminates regulatory t cells to enhance antitumor immune response

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Immune-checkpoint inhibitors show promise in cancer therapy but have limited efficacy in prostate cancer due to an immunosuppressive tumor microenvironment.
• Prostate cancer's immunosuppressive microenvironment is characterized by inhibitory cells like myeloid-derived suppressor cells, mesenchymal stem cells, and regulatory T cells (Tregs).
• Eliminating these immunosuppressive cells is a key strategy to enhance immune-based therapies for prostate cancer.

Purpose of the Study:

• To develop and characterize a novel chimeric protein for selectively targeting and eliminating immunosuppressive cells within the tumor microenvironment.
• To evaluate the efficacy of the chimeric protein in reducing regulatory T cells (Tregs) and enhancing antitumor immune responses.

Main Methods:

• A chimeric protein, IL2-R336A, was engineered by fusing the cytokine IL-2 with a binding-mutant of the bacterial toxin proaerolysin.
• The selective toxicity of IL2-R336A towards IL-2 receptor-expressing cells, particularly Tregs, was assessed.
• The effect of IL2-R336A on Treg depletion in tumor-bearing and non-tumor-bearing mice was evaluated.
• The impact of IL2-R336A on tumor growth and immune response to vaccination and model antigens was investigated.

Main Results:

• The IL2-R336A fusion protein demonstrated selective killing of immunosuppressive Tregs expressing the IL-2 receptor, with minimal impact on other cells.
• IL2-R336A effectively depleted Tregs in both tumor-bearing and non-tumor-bearing mouse models.
• In tumor-bearing mice, pre-treatment with IL2-R336A before vaccination with a GMCSF-expressing CT-26 GVAX vaccine led to reduced tumor growth.
• IL2-R336A enhanced the immune response to a model hemagglutinin antigen in previously tolerized mice.

Conclusions:

• The IL2-R336A fusion protein shows potential as a therapeutic agent for selectively eliminating immunosuppressive Tregs.
• This targeted depletion of Tregs can improve the efficacy of antitumor vaccines by enhancing anti-tumor immune responses.
• IL2-R336A may represent a valuable tool for overcoming immune suppression in prostate cancer and improving treatment outcomes.