SynNotch, A New Generation Of Flexible And Controllable CAR T Therapies (Part 2)

(Posted on Tuesday, May 30, 2023)

Perhaps complex at first glance, in reality synNotch receptors function simply and possess unseen therapeutic potential.

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Chimeric Antigen Receptor T cell (CAR T) therapy is a cell-based treatment that has garnered success in treating blood cancers like large B cell lymphoma, leukemia, and multiple myeloma. However, certain limitations prevent the therapy’s adaptation to other diseases. Recent research suggests an alternative receptor called synNotch may address these problems.

What is SynNotch?

SynNotch is a synthetically engineered version of Notch, a receptor protein present in a variety of animals. This receptor is crucial for cell development. When a Notch receptor receives a signal, it activates a mechanical response that determines the identity and differentiation of unspecialized immune cells. Interestingly, Notch dysfunction is associated with cancers such as leukemia.

Notch activates simply. First, the extracellular portion of the receptor senses and binds to a particular family of proteins found on nearby cells. Binding mechanically pulls the receptor up, exposing a cleavage site to enzymes inside of the cell. The enzymes cut and release a transcription factor into the cytoplasm. The transcription factor then travels to the nucleus, where it attaches to a particular DNA sequence and ultimately influences the expression of certain genes.

With synNotch, the regulatory domain found in the original receptor is kept. However, as illustrated in Figure 1, both the extracellular and intracellular components are customized to achieve a desired response. A new antigen target can be assigned by changing the fusion antibody (single chain variable fragment, scFv) found in the extracellular region. Similarly, fusing a different transcription factor to the receptor can positively or negatively affect any gene of interest.

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Benefits of SynNotch

This modular design has great potential for cell therapy. With this system, researchers can determine who the receptor binds to and what effect is caused—essentially crafting the input and output of a T cell response. CAR T cell appears limited in comparison; even if the antigen target is changed, the cell can only trigger the same signal pathway. Another major difference is that CAR T cells produce cytokines and do not influence gene expression as Notch or synNotch receptors do.

Limitations and Implications 

SynNotch cells, while flexible by design, possess similar limitations to CAR T cells. To this end, the researchers at the University of Pittsburgh developed a universal adaptor that worked not only with CAR T cells, but with synNotch T cells, as well. Ideally, the adaptor would grant synNotch cells the ability to target multiple antigens at the same time or sequentially; to switch targets by introducing a new antibody with the same tag; or to stop or start cell activity by altering the adaptor concentration or introducing tags as a competitive inhibitor.

In the final installment of this series, we will describe how the authors developed their adaptor to work for synNotch cells.

Read the article on Forbes