Van Den Eeckhout et al. demonstrated that treatment with systemic CD8α ALN-1, a fusion protein with a reduced-affinity mutant human IL-1β and a single-domain anti-CD8α antibody, safely delayed tumor growth in subcutaneous B16 melanoma and Lewis lung carcinoma models in CD8+ T cell-dependent manner. CD8α ALN-1 increased epitope spreading and accumulation of functionally potent effector CD8+ T cells in the TDLN and tumor, and improved adoptive cell transfer efficacy. CD8α ALN-1 showed strong synergy with neovasculature-targeted TNF in an IFNγ-dependent manner, leading to complete tumor eradication and protection against rechallenge.
Contributed by Shishir Pant
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 (Activity-on-Target cytokines), which represent fusions between low-activity cytokine mutants and cell type-specific single-domain antibodies. AcTakines deliver cytokine activity to a priori 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.