Engineering opportunities in cancer immunotherapy

Abstract

Immunotherapy has great potential to treat cancer and prevent future relapse by activating the immune system to recognize and kill cancer cells. A variety of strategies are continuing to evolve in the laboratory and in the clinic, including therapeutic noncellular (vector-based or subunit) cancer vaccines, dendritic cell vaccines, engineered T cells, and immune checkpoint blockade. Despite their promise, much more research is needed to understand how and why certain cancers fail to respond to immunotherapy and to predict which therapeutic strategies, or combinations thereof, are most appropriate for each patient. Underlying these challenges are technological needs, including methods to rapidly and thoroughly characterize the immune microenvironment of tumors, predictive tools to screen potential therapies in patient-specific ways, and sensitive, information-rich assays that allow patient monitoring of immune responses, tumor regression, and tumor dissemination during and after therapy. The newly emerging field of immunoengineering is addressing some of these challenges, and there is ample opportunity for engineers to contribute their approaches and tools to further facilitate the clinical translation of immunotherapy. Here we highlight recent technological advances in the diagnosis, therapy, and monitoring of cancer in the context of immunotherapy, as well as ongoing challenges.

Keywords: adoptive T-cell therapy; cancer vaccine; checkpoint blockade; diagnostic tools; immunoengineering.

Fig. 1.

Features of the tumor microenvironment that hinder immunotherapy. To dampen the killing functions of cytotoxic T lymphocytes (CTLs), regulatory T cells (T_regs) secrete TGF-β and IL-10, whereas myeloid-derived suppressor cells (MDSCs) secrete arginase (ARG), nitric oxide (NO), and reactive oxygen species (ROS). Immature or regulatory dendritic cells secrete IL-10 and indoleamine 2,3-dioxygenase (IDO) and can further present antigens to T cells in ways that drive anergy or tolerance, including through overexpression of ligands for the checkpoint molecules PD-1 and CTLA-4. Tumor-associated macrophages (TAMs) also secrete immune suppressive factors and cytokines to block the activity of natural killer (NK) cells and CTLs. Tumor cells and host stromal cells (including fibroblasts and blood and lymphatic endothelium) can also express TGF-β, checkpoint ligands, and FasL to directly cause T-cell apoptosis.