17.3 Synthetic Biology Approaches to Cellular Immunotherapy Engineering 351synapse [30, 31] or stably integrating T cells with DNA constructs that encode
for immunostimulatory cytokines under the control of constitutive or inducible
promoters [32, 33]. Similarly, genetically engineered stem cells have been pro-
grammed to deliver cytotoxic molecules, angiostatic factors, and immunostimu-
latory cytokines to tumor cells [34–36], demonstrating the versatility and
programmability of living cells as therapeutic agents.
Second, unlike static drug molecules, cellular therapeutics can be genetically
programmed to conditionally and dynamically deliver functional outputs in
response to the presence of specific inputs, thereby increasing therapeutic speci-
ficity and efficacy. For example, T cells are naturally programmed to execute
functions ranging from cytotoxicity to immune recruitment only upon encoun-
tering target cells that express antigens recognized by the T-cell receptor (TCR).
T-cell functions vary dynamically with time and are closely coordinated with the
rest of the adaptive immune system, thus enabling a finely modulated response
to disease and infection. In addition to natural TCRs, synthetic CARs that mimic
TCR function and redirect T-cell specificity toward disease targets that are oth-
erwise non-immunogenic have shown great promise in clinical trials [26–29].
Furthermore, T-cell activation can in turn serve as the trigger for downstream
effector outputs. For example, by transgenically expressing the immunostimula-
tory cytokine interleukin-12 (IL-12) gene under the NFAT (nuclear factor of acti-
vated T cells) promoter, researchers have generated melanoma-reactive T cells
that produce IL-12 only upon T-cell activation, thus avoiding the need for sys-
temic IL-12 injections and associated toxicities [33]. As living entities, therapeu-
tic cells have the ability to perform sense-and-respond functions that greatly
enhance treatment specificity and reduce toxic side effects.
Third, unlike chemical pharmaceuticals and biologics, cellular therapeutics have
the potential to establish prolonged proliferation in the patient and provide con-
tinual surveillance against disease relapse without repeated drug administration.
Long-term persistence of therapeutic cells has been shown to be critical in main-
taining complete remission across cancer types in adoptive T-cell therapy [37, 38],
highlighting the importance of this unique characteristic of cellular therapies.
Despite these important advantages, cellular therapeutics still face major chal-
lenges in achieving the level of safety and efficacy required of frontline treatment
options. The use of living cells as therapeutic agents invokes a level of complexity
not previously seen with traditional pharmaceutical development, and the ability
to precisely engineer and stringently regulate therapeutic cells is a critical need
that must be fulfilled in the rise of cellular therapy. The following sections discuss
some of the challenges facing cell-based therapeutics – particularly cell-based
immunotherapies – and highlight solutions that have been developed through
the application of synthetic biology.
17.3 Synthetic Biology Approaches to Cellular
Immunotherapy Engineering
The programmability of living cells to perform diverse functions – natural or
engineered, constitutive or modulated by regulatory systems – is a defining