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CellRapeutics™ Next-Generation TCR-TIL Development Services

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All products and services are For Research Use Only and CANNOT be used in the treatment or diagnosis of disease.

T-cell Receptor Therapy (TCR-T) is an innovative approach that enhances a patient's T-cells, enabling them to more effectively recognize and combat cancer cells. In contrast, tumor-infiltrating lymphocyte (TIL) therapy harnesses the immune cells that have already infiltrated tumors in the body. By combining these two advanced techniques, Creative Biolabs offers a robust CellRapeutics™ Next-Generation TCR-TIL technology that has demonstrated significant efficacy, especially in the treatment of melanoma and specific types of solid tumors.

Introduction

TCR-T and TIL therapy are two advanced forms of cell-based immunotherapy that have garnered significant attention in cancer treatment in recent years. TCR-T enables the T-cells to recognize and attack tumor cells, particularly those that express particular antigens. These TILs often have a strong ability to recognize tumors since they are derived from the tumor microenvironment and can directly target a variety of tumor antigens.

Creative Biolabs combines TCR-T and TIL therapies to harness their potential synergistic effects, enhancing the immune response against tumors. Here are some of the potential technical advantages of this combined approach:

• Multiple Targeting: TILs can recognize a range of antigens present in the tumor, while TCR-T can specifically target defined antigens. This combination can address tumor heterogeneity, reducing the likelihood of tumor evasion.
• Enhanced Immune Response: The integration of both therapies may strengthen the overall immune response, disrupting tumor growth and metastasis.
• Improved Treatment Efficacy: The combined use of these therapies could enhance the overall treatment effect, potentially increasing the rate of complete tumor remission or extending patient survival.

Fig.1 TCR-TIL Cell Construction.^1,3

Services

Currently, Creative Biolabs has established a TCR-TIL technology platform. Our team aims to assist clients in gaining a deeper understanding of TCR-TIL design, development, and production through a range of diverse services, as well as its potential applications in various types of tumors, such as melanoma and lung cancer. In addition, we are continuously exploring solutions to improve the survival time of TCR-TILs and to assess their toxicity, safety, and efficacy.

High-Affinity TCR Development Services

At Creative Biolabs, the development of high-affinity TCRs has emerged as a crucial element in the success of constructing TCR-engineered TILs. This process usually consists of tailored procedures aimed at enhancing the specificity and binding strength of TCRs to specific antigenic targets, like those associated with tumors or infectious diseases.

STEP1: Screening and Cloning of TCR Sequences:

- Isolate mRNA from activated T cells and use reverse transcriptase to convert it into cDNA.

- Employ PCR to amplify the TCR's alpha and beta chains, selecting high-affinity TCR genes.

STEP2: Affinity Engineering of TCRs:

- Modify the TCRs using techniques such as site-directed mutagenesis and random mutagenesis to enhance their affinity for specific antigens.

- Utilize display technologies (such as phage display and yeast display) to screen for TCRs with improved affinity.

STEP3: Transfection and Expression:

- Transfect the modified TCR genes into suitable cell lines (such as 293T or CHO cells) for expression.

- Assess TCR expression levels using techniques such as Western blotting or flow cytometry.

STEP4: Functional Validation:

- Conduct in vitro cytotoxicity assays to evaluate the cytotoxic effects of high-affinity TCR-T cells (e.g., by measuring cytokine secretion through CFSE staining or ELISA).

- Perform in vivo experiments in animal models to observe the anti-tumor efficacy of TCR-T cells.

TCR Optimization Services

In the development of TCR-TIL, optimizing the TCR is a crucial step. The TCR optimization services we offer typically encompass the following aspects:

• TCR Screening and Identification: Utilizing high-throughput screening techniques to identify effective TCRs from tumor-specific antigens. This process involves sourcing TCRs capable of recognizing tumor antigens using cell libraries, synthetic peptide libraries, and other methods.
• TCR Sequence Optimization: Enhancing the sequences of selected TCRs to improve their expression levels, affinity, and specificity within specific host cells. This may include techniques such as point mutations and framework modifications.
• Functional Validation: Conducting in vitro and in vivo experiments to assess the effectiveness of the optimized TCR in recognizing and eliminating target cells. This can involve cytotoxicity assays, cell proliferation studies, and cytokine secretion tests.
• Immunogenicity Assessment: Evaluating the immunogenic potential of the TCR in the host to ensure its safety and efficacy in treatment. It's important to avoid potential autoimmune reactions that could arise.

Fig.2 Analysis of TCR Sequences and the Separation of TCR-Antigen Interaction from CD3 Signaling.^2,3

Advantages

At Creative Biolabs, our TCR-TIL is a promising strategy that may offer new hope for difficult-to-treat solid tumors. This approach has several potential advantages, including:

• Enhanced Anti-Tumor Effect: TCR-T primarily functions by recognizing specific tumor antigens to eliminate cancer cells, while TILs undergo natural selection in the tumor microenvironment and may have a broader recognition capacity for various antigens. TCR-TILs combine these two methods could improve overall tumor identification and eradication.
• Overcoming Antigen Escape: Tumor cells often evade immune surveillance by downregulating specific antigens or through mutations. TCR-TILs can bolster the attack on different tumor antigens, thereby reducing the likelihood of tumor escape.
• Functional Enhancement: TILs have undergone expansion and maturation in the tumor microenvironment, and their integration with TCR-T cells may provide elevated activity and anti-tumor capabilities, particularly within the tumor microenvironment.
• Increased Efficacy and Tolerance: TCR-TIL may synchronize the immune response more effectively, minimizing the immune suppression or resistance that can occur with single-agent treatments, thereby improving overall efficacy and patient tolerance.
• Adaptive Immune Response: TILs benefit from natural selection, allowing them to adjust to dynamic changes in the microenvironment. Meanwhile, TCR-T cells can be designed and optimized for specific targets, making TCR-TILs use a more effective strategy for addressing tumor variability.
• Enhancing Cell Function: Optimizing TCRs can also boost T-cell functionality, such as their proliferation ability, cytokine secretion, and persistence. All of these factors are closely linked to the effectiveness of the treatment.
• Increasing Production Efficiency: Refining TCR design can improve the cell manufacturing process, making in vitro expansion more efficient and stable. This ultimately enhances the accessibility and cost-effectiveness of the treatment.

Creative Biolabs provides TCR-TIL services, an innovative method that utilizes the immune system's strengths to fight cancer more efficiently. Our technology enhances the detection of tumors and harnesses the natural killing abilities of TILs, resulting in a stronger response against tumors. We appreciate your interest and are excited about the possibility of working together on your TCR-TIL projects. Contact us today to find out more or to begin your order!

References

1. Zhang, Yikai, et al. "TCR engineered T cells for solid tumor immunotherapy." Experimental Hematology & Oncology 11.1 (2022): 38.
2. Kapetanovic, Edo, et al. "Engineered allogeneic T cells decoupling T-cell-receptor and CD3 signaling enhance the antitumor activity of bispecific antibodies." Nature Biomedical Engineering (2024): 1-17.
3. Distributed under Open Access license CC BY 4.0, without modification.