Cell Therapy Solutions

Introduction

Adoptive cell therapy (ACT) has led to highly effective cancer treatments for patients who had very few treatment options. It utilizes the patient’s own immune system to attack cancer cells. 

Engineered TCR therapy is a type of ACT that leverages engineered T cell receptors to target tumor specific antigens. This starts with sequencing of the tumor biopsy to identify tumor mutations, and typically, the peripheral blood to uncover the TCR repertoire. 

TCR repertoire sequencing can be done via single cell sequencing or bulk sequencing. Each has it’s own advantages. Bulk sequencing enables you to sample more of the sequence space but information about the alpha-beta TCR pairing is lost. Single-cell sequencing enables you to capture information on the alpha-beta chain pairing and receptor composition. However, single-cell sequencing has a much lower throughput than bulk sequencing.  

How can Twist help me build TCR libraries?

Twist offers TCR libraries that complements both strategies:

Paired Pooled TCR Library (figure 1A)

• Enables you to retain the original alpha-beta chain pairing to maximize hit validation and replicate the TCR repertoire
• This is a good complement to single-cell sequencing where the alpha-beta TCR pairing is known

Combinatorial TCR Library (figure 1B)

• Enables you to shuffle alpha and beta chain pairs to create additional diversity and explore novel combinations beyond the identified repertoire
• This is a good complement to bulk sequencing where the alpha-beta TCR pairing is unknown 
   

Performance Data

The discovery of TCRs is driven by the screening of immune cell repertoires and the re-synthesis of large numbers of potential binders. TCR Libraries can be leveraged to rapidly generate combinations of TCR beta and alpha chains for high throughput screening. With combinatorial TCR libraries, the alpha and beta chains are shuffled together to create a library of greater diversity to integrate the variant space beyond the identified repertoire. With paired pool TCR libraries, explicit alpha and beta chain pairing identified through sequencing are conserved. 

Combinatorial TCR Libraries

Paired Pool TCR Libraries

T Cell Receptor (TCR) Discovery workflow 

Partner with Twist Bioscience to identify and develop novel advanced cell therapies through large-scale, highly diverse T-cell Receptor (TCR) libraries.

We will provide you with highly uniform screening libraries that are precise, user-defined combinations of gene fragments, which enable you to efficiently test comprehensive screening of the desired combinations.

Introduction

Over the last few years, chimeric antigen receptor (CAR) T-cell therapy emerged as a new form of immunotherapy. Novel CAR designs coupled with advances in gene transfer technology and gene editing has opened the door for new cancer therapies. However, there are still many challenges that needs to be tackled to accelerate development.  

CARs consist of a extracellular binding domain, a hinge region, a transmembrane domian, and one or more intracellular domains. Fine-tuning each domain of the CAR is one of the initial steps to improving T cell specificity, antigen recognition, and T cell function. Studies have shown that small modifications to the CAR can have significant impact on the therapeutic outcome. Therefore, it key to have a comprehensive library to interrogate as each CAR construct needs intensive testing. 

Twist has developed a technology to build CAR libraries in a manner that seamlessly shuffles variants of each domain via scarless assembly process. 

How does it work?

Figure1: Each of these domains can consist of several different sequence variants. These domains are synthesized as genes which Twist combines together in a through scarless assembly process to generate a highly diverse library for scaffold optimization. This technology enables the discovery of unique domain combinations that reveal novel functionalities.

Chimeric Antigen Receptor (CAR) Discovery and Optimization Workflow

Each domain of the CAR scaffold influences the functionality of the CAR both independently and synergistically. CAR Libraries serve as a tool to fine-tune each of the modules to uncover codependencies and better understand the impact on T-cell specificity, antigen recognition and T-cell function.

Partner with Twist at any stage of your discovery workflow! 

• Leverage both in vivo and in vitro workflows for binder discovery and optimization
• Leverage our synthetic libraries for scaffold optimization and validation

Fill out our library's submission form and send it to [email protected] for design review. Once the design review is complete, we will provide you with a quote. The price and turnaround time of your combinatorial assembly libraries will vary per project.