Adoptive cell therapy (ACT) has emerged as a highly effective treatment for cancer, particularly for patients with limited treatment options. This innovative approach harnesses the patient’s own immune system to target and attack cancer cells. One form of ACT, known as Engineered TCR therapy, utilizes engineered T cell receptors to specifically target tumor-specific antigens. The process begins with sequencing tumor biopsy samples to identify tumor mutations and analyzing peripheral blood to uncover the TCR repertoire.
TCR repertoire sequencing can be achieved through two main methods: single-cell sequencing and bulk sequencing, each offering unique advantages. Bulk sequencing allows for a broader sampling of the sequence space, but it comes at the cost of losing information about the alpha-beta TCR pairing. On the other hand, single-cell sequencing captures detailed information about alpha-beta chain pairing and receptor composition, but it has a lower throughput compared to bulk sequencing.
The key benefits of Twist’s technology in this context include high diversity and quality in TCR libraries. Combinatorial assemblies can encompass up to 10,000 gene fragment combinations, ensuring a rich and varied representation. NGS-verified libraries guarantee that over 90% of possible variants are present within 10 times of the mean, ensuring reliability and accuracy. The platform also offers customization, allowing users to define combinatorial variants across alpha and beta chains in TCR Libraries.
Twist’s technology is flexible, accommodating sequences up to 1.5 kb in length, and it is designed at scale with diversity across multiple elements of the sequence. This flexibility, combined with high diversity and quality, positions Twist as a valuable partner in advancing Engineered TCR therapy, providing researchers with the tools needed for comprehensive TCR library customization and optimization.
The process of discovering T Cell Receptors (TCRs) involves screening immune cell repertoires and resynthesizing numerous potential binders. TCR Libraries play a pivotal role in this discovery process, enabling the rapid generation of combinations of TCR beta and alpha chains for high-throughput screening.
Two main approaches are employed: Combinatorial TCR Libraries and Paired Pool TCR Libraries. In Combinatorial TCR Libraries (Figure 1a), the alpha and beta chains are shuffled together, creating a library with greater diversity that extends beyond the identified repertoire. On the other hand, Paired Pool TCR Libraries (Figure 1b) preserve the explicit alpha and beta chain pairing identified through sequencing.
The T Cell Receptor (TCR) Discovery workflow involves partnering with Twist Bioscience to identify and develop novel advanced cell therapies using large-scale, highly diverse TCR libraries. Twist provides highly uniform screening libraries, precise user-defined combinations of gene fragments that allow for efficient and comprehensive screening of desired combinations. This partnership facilitates the discovery of novel TCRs, advancing the development of innovative and effective cell therapies for various applications.
Combinatorial TCR Libraries
Paired Pool TCR Libraries
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