A novel treatment for T-cell leukaemias and lymphomas is showing promise after success in research with mice, researchers have reported.
The therapy is an antibody-drug conjugate and combines an antibody that targets the TRBC1 protein, expressed on the surface of T-cell cancers, with the SG3249 anti-cancer drug.
Writing in Nature, researchers from Johns Hopkins University, Baltimore, Maryland, USA, describe how the conjugate uses the antibody to seek out cancer cells that express TRBC1. Those cancer cells go on to ingest the ADC, where SG3249 is released and kills the cancer cells.
Senior study author Dr Suman Paul, assistant professor of oncology at the Johns Hopkins University School of Medicine, said effective therapies for B-cell cancers wipe out both cancerous and noncancerous B cells – but patients still do well even without the immune system B cells that help fight infections.
But if a similar approach is attempted for a T-cell cancer, it would leave patients without a functioning immune system and at high risk of dying from infections, Dr Paul said.
“Not much drug development has happened in this space of T-cell leukaemias and lymphomas,” he said. “We need new therapies for these cancers, but whatever therapies we develop in the space have to be cancer specific. We have to preserve some of the normal T cells and wipe out cancerous T cells at the same time.”
T-cell cancers express either TRBC1 or TRBC2, while normal T cells express a mix of TRBC1 and TRBC2. Selective targeting of TRBC1 can potentially eradicate the normal and cancerous T cells expressing TRBC1 while preserving normal T cells expressing TRBC2, the researchers say.
A recent clinical trial attempted to target TRBC1 cancers using chimeric antigen receptor (CAR) T-cell therapy, but trial investigators reported the CAR T cells were not persisting inside the patients.
For this study, Dr Paul and colleagues found the CAR T cells targeting TRBC1 could be killed by normal T cells, thus limiting their persistence.
This lack of CAR T-cell persistence led the team to try TRBC1 targeting with the use of antibody-drug conjugates, using laboratory mice bearing human T-cell disease.
The team tried two different formulations of conjugates in mouse models of T-cell cancers. After a single injection of one formulation of the treatment, the cancers initially regressed but then recurred.
But after treatment with an anti-TRBC1-SG3249 ADC combination, they observed signs of cancer elimination within seven days and the cancers were eventually undetectable, with no recurrences. The researchers checked the mice for 200 days and the tumours did not return.
They are now working with an industry partner to conduct early-phase safety and efficacy trials in human patients.
Source:
Nichakawade TD, Ge J, Mog BJ, Lee BS, Pearlman AH, Hwang MS, DiNapoli SR, Wyhs N, Marcou N, Glavaris S, Konig MF, Gabelli SB, Watson E, Sterling C, Wagner-Johnston N, Rozati S, Swinnen L, Fuchs E, Pardoll DM, Gabrielson K, Papadopoulos N, Bettegowda C, Kinzler KW, Zhou S, Sur S, Vogelstein B, Paul S. (2024) “TRBC1-targeting antibody–drug conjugates for the treatment of T cell cancers.” Nature, 27 March 2024, doi: 10.1038/s41586-024-07233-2.
Link: https://www.nature.com/articles/s41586-024-07233-2
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