T cell receptor T cell therapy

T cell receptor T cell therapy (TCR-T) is a type of adoptive T-cell therapy that targets some cancers. TCR-T therapies are based on the use and redirection of the T cell receptor (TCR) against specific antigen of interest such as a tumor antigens[1]. TCRs are heterodimers made of alpha and beta peptide chains to recognize MHC-presented polypeptide fragment molecules[2]. Unlike CAR-T, which uses cell surface antigens, TCR-T can recognize MHC's larger set of intracellular antigen fragments. However, TCR-T cell therapy depends on MHC molecules, limiting its usefulness.[1][3][4]

Each T cell's TCR is specific to one antigen and sits on the T cell's surface. The affinity of human TCRs to tumor antigens is relatively low, rendering them unable to recognize and kill tumor cells effectively. The modified T cell has much higher affinity, which enhances both recognition and affinity supporting the recognition of tumor cells.[3]

History

Michael Steinmetz was the first to move TCR genes across T cells. The recipient T cell then recognized a different antigen, enabling the use of these cells to target non-surface antigens.[3]

One clinical trial modified multiple amino acids, increasing the T cell's affinity for New York esophageal squamous cell carcinoma (NY-ESO-1). This TCR was used to attack NY-ESO-1-overexpressing cancers, such as multiple myeloma. 80% of multiple myeloma patients had at least a good clinical response, and 70% had complete or near-complete response.[3]

In 2024, the US Food and Drug Administration approved afamitresgene autoleucel (Tecelra) as the first TCR-T therapy for the treatment of synovial sarcoma.[5]

Process

Appropriate target antigens are identified by substraction. First the entire set of antigens presented by tumor cells is identified. Next, those presented by normal cells are screened out, leaving only those unique to the tumorous cells. Then a TCR phage display library is used to pick TCRs with high affinity and specificity. A preclinical safety test watches for off-target effects and cross-reactivity.[3]

Certain studies have shown that TCR clones can also be identified from a Tumor-infiltrating lymphocytes (TILs) or other T cell clones from patients. Isolated T cell clones are then selected based on their reactivity against specific cell types. TCR can then be sequenced and a DNA construct can be designed based on this sequence. DNA construct can then be virally transduced or electroporated in T cells to lead to the desired TCR expression in order to rewire T cells against wanted cell types.[6][7]

Challenges include target selection, TCR identification, affinity screening, safety, time, and cost.[3]

Most targets are limited by MHC class.

Advances & Challenges

Side effects

Hybridization (mismatch) between exogenous and endogenous chains may induce harmful recognition of autoantigens, triggering graft-vs.-host disease. Increased affinity poses a risk of false targeting.

Target malignancies

Malignant myelomas appear qualified, but the appropriate epitopes have not been identified. Published studies and their target antigens include:

Solid tumors:

In solid tumors local injection is more effective than systemic drug administration, such as injecting T cells into the cerebrospinal fluid in brain tumors. Published studies include:

References

  1. ^ a b Golikova EA, Alshevskaya AA, Alrhmoun S, Sivitskaya NA, Sennikov SV (4 October 2024). "TCR-T cell therapy: current development approaches, preclinical evaluation, and perspectives on regulatory challenges". Journal of Translational Medicine. 22 (1) 897. doi:10.1186/s12967-024-05703-9. ISSN 1479-5876. PMC 11451006. PMID 39367419.
  2. ^ Shah K, Al-Haidari A, Sun J, Kazi JU (13 December 2021). "T cell receptor (TCR) signaling in health and disease". Signal Transduction and Targeted Therapy. 6 (1) 412. doi:10.1038/s41392-021-00823-w. ISSN 2059-3635. PMC 8666445. PMID 34897277.
  3. ^ a b c d e f Zhao L, Cao YJ (2019). "Engineered T Cell Therapy for Cancer in the Clinic". Frontiers in Immunology. 10: 2250. doi:10.3389/fimmu.2019.02250. PMC 6798078. PMID 31681259.
  4. ^ "TCR Vs. CAR-T: What is CAR-T Cell, TCR Therapy, and What are They Used For?". Akadeum Life Sciences. 23 November 2020. Retrieved 14 January 2022.
  5. ^ "Adaptimmune Receives U.S. FDA Accelerated Approval of Tecelra (afamitresgene autoleucel), the First Approved Engineered Cell Therapy for a Solid Tumor" (Press release). Adaptimmune. Retrieved 3 August 2024.
  6. ^ Terada K, Kondo K, Ishigaki H, Nagashima A, Satooka H, Nagano S, et al. (March 2022). "Isolation of TCR genes with tumor-killing activity from tumor-infiltrating and circulating lymphocytes in a tumor rejection cynomolgus macaque model". Molecular Therapy - Oncolytics. 24: 77–86. doi:10.1016/j.omto.2021.12.003. PMC 8717465. PMID 35024435.
  7. ^ Rosenberger L, Hansmann L, Anastasopoulou V, Wolf SP, Drousch K, Moewes C, et al. (2 May 2025). "Selection of therapeutically effective T-cell receptors from the diverse tumor-bearing repertoire". Journal for ImmunoTherapy of Cancer. 13 (5): e011351. doi:10.1136/jitc-2024-011351. ISSN 2051-1426. PMC 12049912. PMID 40316304.

Further reading

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