Synthetic Biology: Immunotherapy by Design

Abstract

Cellular immunotherapy holds great promise for the treatment of human disease. Clinical evidence suggests that T cell immunotherapies have the potential to combat cancers that evade traditional immunotherapy. Despite promising results, adverse effects leading to fatalities have left scientists seeking tighter control over these therapies, which is reflected in the growing body of synthetic biology literature focused on developing tightly controlled, context-independent parts. In addition, researchers are adapting these tools for other uses, such as for the treatment of autoimmune disease, HIV infection, and fungal interactions. We review this body of work and devote special attention to approaches that may lend themselves to the development of an "ideal" therapy: one that is safe, efficient, and easy to manufacture. We conclude with a look toward the future of immunotherapy: how synthetic biology can shift the paradigm from the treatment of disease to a focus on wellness and human health as a whole.

BioLogic, a parallel approach to cell-based logic gates

“…A cell-based logic network consists of engineered cells producing an output macromolecule only if the corresponding pattern of inputs is present. The mechanism of analysis is commonly based on the use of transcriptional regulators, transcription factors, polymerases, receptors or recombinases (Brenner et al, 2018). Some examples of genetic circuits mimicking computational behavior are toggle switches, oscillators, boolean logic gates, feedback controllers and multiplexers.…”

DNA-scaffolded biomaterials enable modular and tunable control of cell-based cancer immunotherapies

“…To increase the tumor targeting specificity and 3 avoid "on-target, off-tumor" toxicity in bystander healthy tissues 28 , CAR-T cells have been engineered with combinatorial antigen AND-gate activation control that requires sensing two antigens on a target cell to initiate killing. The clinical application of this strategy, however, requires systematic identification of tumor specific antigen combinations and would also benefit from better control of cell activity 27,29 .Biomaterials functionalized with modulatory biomolecules at pre-specified densities have been shown to communicate with and control therapeutic immune cells both ex vivo and in vivo 1-15 . For example, synthetic materials have been functionalized with agonistic antibodies for CD3 and CD28 to drive ex vivo T cell expansion 25,26 .However, biodegradable materials 25 with optimized material structure/composition and controlled surface moiety loading can provide unique opportunities to improve the ease of manufacturing and the quantity and quality of T cells produced.…”

“…Cumulatively, these properties suggest that AICE could aid in manufacturing for ACT by improving the ease-of-production and fine-tuning the yield and phenotype of the therapeutic cell product.We and other groups have developed strategies to engineer T cells with multiple receptors to detect combinations of antigens [27][28][29] . All prior combinatorial antigen recognition systems have targeted combinations of antigens expressed on tumor cells and/or tumor-related cells 27,29 . Here, we demonstrate a method to engineer T cells to recognize combinations of endogenous and orthogonal antigens presented by tumor cells and biocompatible materials, respectively.…”

“…However, for CAR T cells to fulfill their promising potential, particularly for targeting solid tumors 17,18 , important challenges must be overcome to improve both efficacy [17][18][19][20] and safety [21][22][23][24] . For engineered anti-tumor T cells to achieve durable tumor remission in patients, a demanding manufacturing process is required to ensure the quantity and quality of the cell product for therapeutic use 1,[25][26][27] . To increase the tumor targeting specificity and avoid "on-target, off-tumor" toxicity in bystander healthy tissues 28 , CAR-T cells have been engineered with combinatorial antigen AND-gate activation control that requires sensing two antigens on a target cell to initiate killing.…”

“…To increase the tumor targeting specificity and avoid "on-target, off-tumor" toxicity in bystander healthy tissues 28 , CAR-T cells have been engineered with combinatorial antigen AND-gate activation control that requires sensing two antigens on a target cell to initiate killing. The clinical application of this strategy, however, requires systematic identification of tumor specific antigen combinations and would also benefit from better control of cell activity 27,29 .…”