Armoring T Cells with Engineered Fusion Proteins Enhances Therapeutic Efficacy Against Hematological and Solid Tumors

Adoptive cell therapy (ACT) is a promising immunotherapy treatment option that uses genetically modified immune cells (T cells) to eliminate tumors. This approach uses the patients’ own immune cells to generate a “living drug” and can avoid the toxic side effects of other common therapies, such as radiation or chemotherapies. However, the tumor microenvironment (TME) can establish several obstacles to protect the tumor from T cells, including delivery of inhibitory and death signals that shut down T cells, usurping metabolic nutrients, and recruiting and/or converting immune cells to inhibitory phenotypes that block the T cell response. Costimulatory signals delivered by surface-bound receptors can initiate gene expression programs that address multiple issues in the TME by mechanisms such as lowering the threshold of activation, altering metabolic programming, and reducing exhaustion. We develop engineering strategies, fusion proteins (FPs), that combine the ectodomain of one receptor with a different intracellular costimulatory signaling domain. Here we describe how intentionally engineered fusion protein can “armor” T cells against multiple obstacles and significantly improve therapeutic efficacy against hematological and solid tumors.

Learning Objectives:

1.     Identify 3 obstacles that inhibit the immune cell response to cancer.
2.     List 3 aspects of T cells antitumor function that can be improved with costimulatory signals.
3.     Explain how fusion proteins can improve T cell therapy.