Context-dependent cancer immunotherapy

Cancer cells actively suppress and evade the immune system in order to survive. While cytokines with broad immuno-stimulatory activity can increase the anti-tumor immune response, many have significant dose-limiting toxicities.Cytokines which act when and where they’re needed have the potential to amplify the anti-tumor immune response while reducing systemic toxicity.

Cytokines as therapeutics

The cytokines IL-2 and IFN-α received FDA approval three decades ago. Although efficacious in a subset of cancer patients, widespread usage of these treatments has been limited by toxicity.

We are developing cytokine drugs that are only active following binding to a specified target. Targeted, locally activated cytokine drugs will be more effective than systemically active native or attenuated cytokines.

PD-L1-Dependent IFN-α

PD-L1-dependent IFN-α will target tumor-localized immune cells while limiting adverse systemic effects.

Sensor component:

Antibody binding domain directed against PD-L1

Elevated and dysregulated expression of PD-L1 allows tumors to evade the
anti-tumor immune response. PD-L1 is expressed on both tumor cells and immune cells within the tumor microenvironment. Elevated PD-L1 expression is correlated with a poor prognosis in a variety of solid tumors.

Therapeutic component:

Interferon alpha (IFN-α)

IFN-α increases MHC-I expression on tumor cells, drives innate immune cell activation and cross-presentation, and potentiates
T-cell effector function. Recombinant IFN-α has demonstrated efficacy in melanoma and renal cell carcinoma, but its clinical usage is limited by adverse side effects.

PD-1-Dependent IL-2

PD-1-Dependent IL-2 will target PD-1+ tumor-specific T-cells while remaining inactive on the majority of T-cells in the periphery, which do not express PD-1.

Sensor component:

Antibody binding domain directed against PD-1

PD-1 expression identifies activated tumor-reactive T cells, whereas it is absent on the majority of T cells in circulation. Directing IL-2 activity specifically to PD-1+ T cells has the potential to stimulate the anti-tumor T cell response while minimizing systemic toxicity.

Therapeutic component:

Interleukin 2 (IL-2)

IL-2 promotes the growth and differentiation of activated T-cells and natural killer (NK) cells. High-dose IL-2 is approved for the treatment of cancer, but its clinical usage is limited by toxic side effects.