Researchers at the Johns Hopkins Kimmel Cancer Center's Ludwig Center developed a new treatment that selectively targets TRBC2-positive T-cell cancers, expanding a precision approach they established in 2024 for TRBC1-positive tumors.
The therapy, an antibody-drug conjugate, targets a protein expressed on the surface of T-cell cancers to deliver a cancer cell-killing drug.
The work, published Dec. 22 in Nature Cancer, provides a long-sought therapeutic option for half of T-cell lymphomas and leukemias that express the TRBC2 variant of the T-cell receptor.
T-cell lymphomas and leukemias affect roughly 100,000 people worldwide each year. These T-cell malignancies, rare and scientifically complex, have received far less pharmaceutical investment than B cell leukemias and lymphomas and have fewer treatment options. As a result, adults with relapsed T-cell cancers have five-year survival rates of 7% to 38%.
"There is a challenging situation," says senior author Suman Paul, M.B.B.S., Ph.D., assistant professor of oncology, "because 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."
"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," Paul explains. "We have to be mindful that it has to get rid of the cancer, but it cannot completely get rid of the normal T cells."
One way to achieve this balance is to target TRBC1 or TRBC2, two mutually exclusive genetic variants of the T-cell receptor. Normal T cells are a mix of TRBC1-positive (~40%) and TRBC2-positive (~60%) populations, but each T-cell cancer expresses only one of the two variants. Selectively targeting the cancer-associated TRBC variant preserves approximately 40%–60% of normal T cells. In 2024, the team published findings on the first TRBC1-targeting therapeutic antibody However, until now, no TRBC2-specific therapeutic antibody existed, leaving half of the patients without an equivalent approach.
In the new study, the researchers used a phage-displayed antibody library, a powerful tool used to discover new antibodies, to create JX1.1, a new antibody that recognizes only the TRBC2 protein target and not 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.
Researchers then linked the new JX1.1 antibody to the cancer-cell killing drug pyrrolobenzodiazepine to generate an antibody-drug conjugate (ADC). In laboratory studies using cancer cell lines and animal models, they found the new ADC to be highly specific to TRBC2 cancers, clearly distinguishing between TRBC2-positive and TRBC1-positive normal T cells. The ADC killed TRBC2-positive cancer cells, leading to robust tumor regression in animal models with minimal toxicity. All JX1.1-treated mice sustained elimination of detectable cancer throughout the entire follow-up period of 150 days.
"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," says Paul.
Other researchers participating in the study were Jiaxin Ge, Joshua Urban, Sarah DiNapoli, Bum Seok Lee, Taha Ahmedna, Tushar Nichakawade, Brian Mog, Steve Lu, Xuyang Li, Nikita Marcou, Stephanie Glavaris, Jacqueline Douglass, Jin Liu, Maximilian Konig, Evangeline Watson, Maria Popoli, J. David Peske, Sima Rozati, Cole Sterling, Nina Wagner-Johnston, Richard Ambinder, Kathy Gabrielson, Charles Mullighan, Nickolas Papadopoulos, Chetan Bettegowda, Drew Pardoll, Shibin Zhou, Surojit Sur, Kenneth Kinzler, and Bert Vogelstein.
The research was supported by grants from the Virginia and D.K. Ludwig Fund for Cancer Research, Lustgarten Foundation for Pancreatic Cancer Research, Commonwealth Fund, Bloomberg–Kimmel Institute for Cancer Immunotherapy, Bloomberg Philanthropies and National Institutes of Health (NIH) Cancer Center Support Grant P30 CA006973, CA021765, and R35 CA197695 NIH grants T32 GM136577 and P30CA51008, National Cancer Institute Grants K08CA270403 and R37 CA230400, National Institute of Allergy and Infectious Diseases grant 1R21AI176764-01, National Institute of General Medical Sciences grant T32GM007057-47, Blood Cancer United (formerly the Leukemia & Lymphoma Society), Translation Research Program award, the American Society of Hematology Scholar award and the Swim Across America/Baltimore Translational Cancer Research award, the Jerome Greene Foundation, the Cupid Foundation, and the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital.
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.
