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T cells targeted to TdT selectively kill lymphoblastic leukemia cells

As one of the leading causes of death in humans, cancer has long been an important research issue for scientists from all over the world. According to a recent perspective published in Nature Reviews Clinical Oncology by researchers from the International Agency for Research on Cancer, 34 million new cancer cases will occur annually by 2070 if no additional cancer control programs are implemented, doubling 2020’s incidence (Isabelle et al., 2021). There is a pressing need to discover efficient cancer preventive and treatment methods.

Traditional cancer treatments are mainly surgery, radiotherapy, and chemotherapy. However, as medical science advances, novel immunotherapies continue to emerge and be incorporated into the existing strategies, providing additional potential treatment options for cancer patients.

Limitations of prevailing cancer treatments

Because of their limited therapeutic potential, most current cancer treatments are extremely unsatisfactory. To avoid injuring healthy tissues, surgery and radiation can only be used in limited cases where tumor cells can be seen in imaging studies. Chemotherapy has been widely used in clinics due to its inherent simplicity and convenience as a current mainstay cancer treatment. The issue, however, is its limited efficiency in drug administration, nonspecific drug distribution, and underlying side effects such as hair loss, weakness, and immune depression, as chemical agents can be poisonous to both normal cells and malignant tumors. Traditional treatments for malignant cells, just like battles in human history causing loss of lives from both sides, result in the death of many non-cancer cells.

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T cells targeted to TdT selectively kill cancer cells

Progress regarding precise cancer medication has been made by scientists from Oslo University Hospital. They reported recently in Nature Biotechnology that patient-derived acute lymphoblastic leukemia (ALL) cells of B- and T-cell origin could be exclusively and efficiently destroyed in vitro and in three mouse models by T cells transduced with T-cell receptors (TCRs) targeting peptides from terminal deoxynucleotidyl transferase (TdT) (Ali et al., 2021). TdT is an appealing cancer target since it is highly and homogeneously expressed in 80–94% of B-and T-ALLs, but only expressed transiently during normal lymphoid development, minimizing the off-target toxicity of TdT-specific T cell therapy.

In this study, T cells genetically engineered in the lab to express a TCR recognizing TdT were injected into the blood of mice. Bioluminescence imaging results obtained 21 days after injection showed that T cells can track and eliminate leukemia cells spread in different organs of the mice with the help of the therapeutic TCR recognizing TdT. In addition to the remarkable efficacy, the researchers also found that these T cells had no adverse effect on the development of normal B cells, T cells, or new blood cells, suggesting the safety of the treatment.

The findings presented in this report provide evidence of a potential TCR-modified T cell therapy targeting TdT for lymphoblastic leukemia. Moreover, researchers are planning to apply the same technology to developing therapeutic TCRs for other forms of cancer.

Genscript helped to synthesize and clone the identified TCRs involved in this research.


Soerjomataram, Isabelle, and Freddie Bray. "Planning for tomorrow: global cancer incidence and the role of prevention 2020–2070." Nature Reviews Clinical Oncology (2021): 1-10.

Ali, M., Giannakopoulou, E., Li, Y. et al. "T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes". Nat Biotechnol (2021). https://doi.org/10.1038/s41587-021-01089-x

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