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Engineering T Cell Receptors To Reduce The Risk Of Adverse Side Effects In Immunotherapy

Engineered T cells represent a new and novel approach to target cancer. By introducing unique antigen targeting molecules, we can redirect T cells to locate and destroy cancer cells within the body.

Researchers have been studying ways to use T cells, at the heart of cellular immunity, and the body’s immune system to fight cancer since the 1980s. The antigen targeting molecules in these early studies were tumor-specific T cell receptors (TCRs) targeting tumor-associated peptides presented on the cell surface – but the results revealed a challenge researchers are still working to solve. While TCRs can target peptides of specific disease indications, there is also the potential for autoimmune toxicity. If not carefully controlled, TCRs can direct T cells to healthy cells as well as cancer cells, with potentially fatal consequences.

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The process through which the TCR identifies its target, as we understand now, is far more complex than once believed. There are a number of things to consider including utilization of complementarity determining region (CDR) loops, the role of the target peptide/antigen, and the structural complexities of multi-component signaling.

Our approach aims to modify the physical properties of tumor-specific, clinically relevant TCRs by perturbing their structure. In the context of cell therapy, the objective is to improve the ‘fit’ between the target antigen and the TCR. This structure-guided approach to T cell engineering differs from other brute force methods, which aim to screen thousands of TCRs to identify the one with desired properties.

The use of this method allows us to do something very unique: modulate specificity. Because we study the structural properties of these target antigens, it is possible for us to design TCRs with complementary features, similar to a peg in a hole. Therefore, this technique allows us to not only identify TCRs with poor antigen specificity (and thus, be dangerous as a therapeutic) but mitigate such unwanted recognition by improving complementarity with the tumor-associated antigen.

However, a challenging component of a structure-guided design strategy is the construction of accurate computational models. These models not only have to predict the correct conformation of the redesigned TCR but must also predict the measured impact on antigen recognition.

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Regardless, the benefits of a structure-guided strategy combine to result in a method that it is disease-agnostic. Once you have constructed a model that accounts for the unique elements of TCR recognition, you can deploy it against a wide array of cancer types and diseases. Most of our work emphasizes melanoma, but we have deployed our model to improve TCRs targeting myeloma and lymphoma as well.

With the T cell therapy industry continuing to grow and evolve at a rapid pace, we saw an opportunity to commercialize our research and form a company. In August 2017, we started Structured Immunity with a clear mission: to accelerate and improve the development of TCRs for T cell therapies. We partner with leading biopharmaceutical companies and deploy our technology to optimize their receptors.

Although the FDA has approved T cell therapies using other antigen targeting molecules (Chimeric Antigen Receptors, or CARs), these molecules have limited applicability to solid tumors. Researchers are actively studying TCRs to treat these diseases, but the identification of safe TCRs hinders this next development of cell therapy. By leveraging our novel approach to engineering TCRs, we hope to support the next generation of T cell therapies focused on solid tumors.

This article is based on work conducted by Brian Baker from the University of Notre Dame with Tim Riley and David Hardwicke from Structured Immunity.

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