Researchers at the Johns Hopkins Kimmel Cancer Center’s Ludwig Center have unveiled a groundbreaking new treatment targeting TRBC2-positive T-cell cancers. This development builds on a precision approach first established in 2024 for TRBC1-positive tumors. The therapy, an antibody-drug conjugate, aims to selectively target a protein found on the surface of T-cell cancers, delivering a potent cancer cell-killing drug directly to its target.
The findings, published on December 22 in Nature Cancer, offer a long-sought therapeutic option for approximately half of T-cell lymphomas and leukemias that express the TRBC2 variant of the T-cell receptor. These types of T-cell malignancies affect around 100,000 people globally each year. Despite their rarity and complexity, T-cell cancers have historically received less pharmaceutical investment compared to B-cell leukemias and lymphomas, resulting in fewer treatment options and dismal five-year survival rates ranging from 7% to 38% for adults with relapsed T-cell cancers.
Challenges in T-Cell Cancer Treatment
According to Dr. Suman Paul, M.B.B.S., Ph.D., assistant professor of oncology and senior author of the study, the treatment of T-cell cancers presents unique challenges. “Unlike B-cell therapies, where eliminating both cancerous and healthy B cells is tolerable, therapies targeting T cells must preserve enough normal T cells for patients to survive infections,” Paul explains. “The tricky part is that if the drug kills both the T-cell lymphoma and the normal T cells, then it’s very hard for that person to survive.”
To address this, the researchers focused on targeting TRBC1 or TRBC2, two mutually exclusive genetic variants of the T-cell receptor. Normal T cells are composed of approximately 40% TRBC1-positive and 60% TRBC2-positive populations. Each T-cell cancer, however, expresses only one of these variants. By selectively targeting the cancer-associated TRBC variant, the therapy preserves a significant portion of normal T cells.
Innovative Antibody Development
In their latest study, the team utilized a phage-displayed antibody library to create JX1.1, a new antibody that specifically recognizes the TRBC2 protein target without affecting the similar TRBC1 protein. “Our antibody was developed using SLISY, a next-generation sequencing-based platform for rapid identification of antibody candidates from a phage library,” says Ken Kinzler, Ph.D., Barry Family Professor in Oncology and director of the Ludwig Center.
The researchers then linked the JX1.1 antibody to the cancer-cell killing drug pyrrolobenzodiazepine, forming an antibody-drug conjugate (ADC). Laboratory studies using cancer cell lines and animal models demonstrated the ADC’s high specificity to TRBC2 cancers, effectively distinguishing between TRBC2-positive cancer cells and TRBC1-positive normal T cells. The ADC led to significant tumor regression in animal models with minimal toxicity. Notably, all JX1.1-treated mice sustained elimination of detectable cancer throughout a 150-day follow-up period.
A New Era in T-Cell Cancer Treatment
“The development of TRBC1 and TRBC2 antibodies together now provides a conceptual ‘matched set’ of precision tools for the great majority of patients with T-cell cancers,” Paul states. This advancement marks a significant step forward in the treatment of T-cell malignancies, offering hope to patients who previously had limited options.
The study was conducted by a team of researchers including Jiaxin Ge, Joshua Urban, Sarah DiNapoli, and others. The research received support from various grants, including those from the Virginia and D.K. Ludwig Fund for Cancer Research, Lustgarten Foundation for Pancreatic Cancer Research, and the National Institutes of Health (NIH), among others.
Ge, Nichakawade, Li, Konig, Papadoulos, Pardoll, Zhou, Kinzler, Vogelstein, and Paul are inventors of technologies described in this study. These arrangements have been reviewed in accordance with Johns Hopkins policies.
This breakthrough represents a significant stride in the fight against T-cell cancers, providing a promising new avenue for treatment. As researchers continue to refine these therapies, the potential for improved outcomes for patients with T-cell malignancies grows ever more promising.
