| Year | Reference |
|---|---|
|
2021
|
Selective IL-1 activity on CD8 T cells empowers antitumor immunity and synergizes with neovasculature-targeted TNF for full tumor eradication.
Journal for immunotherapy of cancer
2021 Nov;9: e003293
|
BACKGROUND: Clinical success of therapeutic cancer vaccines depends on the ability to mount strong and durable antitumor T cell responses. To achieve this, potent cellular adjuvants are highly needed. Interleukin-1β (IL-1β) acts on CD8 T cells and promotes their expansion and effector differentiation, but toxicity and undesired tumor-promoting side effects hamper efficient clinical application of this cytokine.
METHODS: This 'cytokine problem' can be solved by use of AcTakines (tivity-on-rget cyto), which represent fusions between low-activity cytokine mutants and cell type-specific single-domain antibodies. AcTakines deliver cytokine activity to selected cell types and as such evade toxicity and unwanted off-target side effects. Here, we employ subcutaneous melanoma and lung carcinoma models to evaluate the antitumor effects of AcTakines.
RESULTS: In this work, we use an IL-1β-based AcTakine to drive proliferation and effector functionality of antitumor CD8 T cells without inducing measurable toxicity. AcTakine treatment enhances diversity of the T cell receptor repertoire and empowers adoptive T cell transfer. Combination treatment with a neovasculature-targeted tumor necrosis factor (TNF) AcTakine mediates full tumor eradication and establishes immunological memory that protects against secondary tumor challenge. Interferon-γ was found to empower this AcTakine synergy by sensitizing the tumor microenvironment to TNF.
CONCLUSIONS: Our data illustrate that anticancer cellular immunity can be safely promoted with an IL-1β-based AcTakine, which synergizes with other immunotherapies for efficient tumor destruction.