TCR-T Cell Therapy: A Promising Approach in Cancer Treatment

T-cell receptor (TCR)-engineered T cell therapy is a new frontier in cancer treatment. It leverages the immune system's ability to recognize and destroy specific targets. TCR-T cells offer the potential for precise and lasting elimination of cancer cells. This blog post will explore the mechanisms of TCR-T cell therapy, its advantages and limitations, and the ongoing advancements in this field.

How TCR-T Cells Work

Unlike chimeric antigen receptor (CAR)-T cell therapy, which targets surface proteins on cancer cells, TCR-T cells target fragments of tumor-associated antigens (TAAs) that reside inside cancer cells. These fragments are presented on the surface of antigen-presenting cells (APCs) via major histocompatibility complex (MHC) molecules. This recognition process allows TCR-T cells to target a wider range of antigens within cancer cells.

The development of TCR-T cell therapy involves isolating a patient's T cells, introducing a gene encoding a specific TCR that recognizes the targeted TAA, and then reintroducing the modified T cells back into the patient. These engineered T cells can then recognize and eliminate cancer cells expressing the targeted TAA.

TCR-based therapeutics recognize peptide/MHC antigens (red and pink) on cells by utilizing either TCRs (light blue) or TCRm antigen-binding domains (green). Left: Soluble ImmTAC molecules bind peptide/MHC on cancer cells via alpha/beta TCR heterodimer similar to membrane-bound TCR and redirect the T cells by engaging extracellular CD3-epsilon (purple) via an anti-CD3 scFv. Right: TCRm mAb recognize peptide/MHC complex via its variable region (green) and to engage effector cells such as NK cells and macrophages to elicit Fc-receptor (orange) mediated ADCC or ADCP. TCRm CAR and bispecific mAb leverage TCRm-derived scFv to harness T cell effector function via engagement with intracellular CD3-zeta (blue) or extracellular CD3-epsilon (purple), respectively.

Advantages of TCR-T Cell Therapy

  • Broader targeting: TCRs can recognize a wider variety of antigens compared to CARs, potentially leading to more precise therapy and reduced side effects.
  • Targeting internal antigens: TCR-T cells can target mutations within cancer cells, offering the possibility of eliminating tumors that lack surface antigens.
  • Potential for memory response: TCR-T cells may develop a memory response against the targeted antigen, leading to long-term tumor control.

Different T cell-based immunotherapies. Advantages and disadvantages of T cell-based therapies including, (i) chimeric antigen receptor (CAR) T or CAR cytokine-induced killer (CAR-CIK) cells, (ii) TCR-engineered T (TCR-T) cells, and (iii) conventional tumor-infiltrating lymphocytes (TILs). The main step during the production process of CAR T/CIK cell therapy, TCR-T therapy, and conventional TIL therapy is CAR transduction, TCR engineering, and TIL enrichment, respectively.

Challenges and Considerations

  • MHC restriction: TCR recognition relies on MHC presentation, which may limit therapy to patients with compatible MHC alleles.
  • Identifying ideal TCRs: Isolating and engineering highly effective and specific TCRs remains a challenge.
  • Manufacturing complexity: The manufacturing process for TCR-T cells can be complex and time-consuming, potentially hindering widespread use.

Challenges in the clinical application of neoantigen TCR-T-cell therapy. a Low neoantigen load results in a lack of suitable neoantigen targets. b At present, the accuracy of neoantigen prediction technology is limited. c Downregulation of MHC expression causes tumor cells to lose neoantigen targets. d The loss of pMHC molecules leads to the interruption and reduction of neoantigen presentation. e The expression of adhesion molecules and stroma-rich and abnormal blood vessels in tumor tissues is downregulated, which limits the effective penetration of T cells. f Immunosuppressive tumor microenvironments inhibit T-cell function. g The technical bottleneck of ACT leads to the production of neoantigen-specific T cells. h Tumor heterogeneity leads to the singleness of specific tumor therapeutic targets and the absence of universal neoantigen targets. i The neoantigen epitopes developed thus far are mainly for HLA-A2 targets.

The Future of TCR-T Cell Therapy

Researchers are actively working to address the limitations of TCR-T cell therapy. These efforts include:

  • Developing universal TCRs: Engineering TCRs that function independently of MHC restriction to broaden applicability.
  • In silico TCR design: Utilizing computational tools to predict and design high-affinity, tumor-specific TCRs.
  • Next-generation manufacturing techniques: Streamlining manufacturing processes to improve efficiency and affordability.

Clinical trials exploring TCR-T cell therapy for various cancers are ongoing and demonstrating promising results. As research progresses in TCR identification, manufacturing processes, and overcoming MHC restrictions, TCR-T cell therapy holds immense potential as a targeted and potentially curative approach in cancer treatment.

The development of TCR-T cell therapy relies on robust research and development efforts, including the use of high-quality reagents for cell engineering and analysis. Companies like Maxanim are playing a crucial role in this progress by providing these essential reagents.

Learn more About TCR & T Cell in This Video:



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TCR-T Cell Therapy: A Promising Approach in Cancer Treatment
Gen store June 18, 2024
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