A fusion protein that inhibits TGF-β signaling and enhances activation of CD8+ T cells and natural killer (NK) cells with applications in cancer immunotherapy, treatment of chronic viral infections, and cell therapy.
- Preserves the function of each component, blocking TGF-β signaling while enhancing Interleukin 15 (IL-15) pro-immune effects on CD8+ T cells and NK cells.
- More effective than IL-15 or TGF-β neutralization strategies alone or in combination.
- Drives CD8+ (killer) T cell and NK cell proliferation, activation, and cytotoxicity ex vivo without need of T cell receptor (TCR) crosslinking or Dynabead pre-activation.
Immunotherapy enhances the body's own immune system's ability to fight disease. Ranging from antibody-based therapies to autologous cell transfers, immunotherapy has proven to be advantageous in the clinic, especially in the treatment of cancer. However, current immunotherapy options for cancer have limited effectiveness and are often utilized in later stages of treatment. As many immunotherapy treatments require expanding immune cells ex vivo, the need exists for alternative strategies to stimulate immune cell proliferation.
IL-15 is a pro-inflammatory cytokine that induces proliferation of NK cells and helps preserve memory T cells. The sushi domain of the IL-15 receptor can enhance the effect of IL-15 by increasing the binding of IL-15 with the IL-15 receptor on immune cells. The TGF-β is overexpressed by many different kinds of tumor cells and plays a role in cancer cell metastasis and immune system evasion. The investigators created a protein fusion of Interleukin 15 with Sushi to TGF-β receptors, named FIST-15. By connecting these components by single amino acid linkers, the fusion protein may prevent TGF-β signaling from suppressing the local immune response to a tumor while also activating IL-15-stimulated anti-cancer immune cells. FIST-15 has potential as a protein therapeutic for treating cancer, chronic viral infections, or as a reagent for ex vivo NK and CD8+ (killer) T cell expansion.
In vitro proof-of-principle experiments have been performed in both CD8+ (killer) T cells and natural killer (NK) cells and in vivo animal study data is available.