350 17 Synthetic Biology in Immunotherapy and Stem Cell Therapy Engineering
instabilities that enable them to escape individual therapeutic strategies through
genetic hypermutation [12]. Furthermore, in cases such as glioblastoma, dis-
eased cells can be situated in a protected niche (e.g., behind the blood-brain bar-
rier (BBB)) that is both inaccessible to chemical and biological therapeutics and
incompatible with complete surgical resection [13]. Finally, diseased cells often
closely resemble healthy tissues on the surface and lack unique molecular mark-
ers that allow precise identification by drug molecules. As a result, strategies
including chemotherapy and antibody therapeutics often lead to severe off-tar-
get or “on-target, off-tumor” toxicities [5, 14].
Complex, dynamic diseases call for a new category of therapeutics that can
actively sense and process multiple input signals and respond to changing
disease landscapes with multipronged therapeutic outputs [1–4]. Cellular thera-
pies represent a new platform for the treatment of currently intractable diseases.
In particular, cell-based immunotherapy has made major strides in the past dec-
ade in the treatment of cancer, viral infections, and autoimmune diseases [15–23]
(Table 17.1). In August 2017, T cells that have been genetically modified to express
tumor-targeting chimeric antigen receptors (CARs) became the first gene therapy
to gain approval from the U.S. Food and Drug Administration (FDA) for cancer
treatment, highlighting the potential of cellular therapy as a novel treatment
option for advanced malignancies.17.2 Rationale for Cellular Therapies
Cellular therapies – that is, the use of living cells as the therapeutic agent – have a
number of distinctive properties that are well suited to the treatment of complex,
dynamic diseases. First, mobile living cells are significantly more versatile than
single molecules in the type and number of effector functions that can be exe-
cuted. Cellular therapeutics can be engineered to serve both as independent
actors that directly eradicate diseased cells or infectious agents and as payload
carriers that deliver therapeutic molecules to a targeted site. For example, cyto-
toxic T cells expressing surface-bound receptors that direct T cells toward tumor
antigens have shown clinical efficacy in treating melanoma [24, 25] and B-cell
leukemia [26–29] through direct killing of cancer cells. Antitumor functions can
be further enhanced by cellular engineering, such as decorating T-cell surfaces
with nanoparticles to specifically deliver drug molecules to the immunologicalTable 17.1 Major categories of cell-based immunotherapies and application areas currently
under investigation.Cell type Major application areasEffector and memory T cells Cancers, viral infections
Regulatory T cells Autoimmune diseases, inflammatory diseases
Myeloid-derived suppressor cells Autoimmune diseases, inflammatory diseases
Dendritic cells Cancer vaccines
Natural killer cells Cancers, viral infections