Targeted therapies mediated by antibodies and chimeric antigen receptor (CAR) T cells improve survival in patients with solid tumors and hematological malignancies. Recently, in a research report titled "TRBC1-targeting antibody–drug conjugates for the treatment of T cell cancers" published in the international journal Nature, scientists from Johns Hopkins University School of Medicine and other institutions have developed a new treatment for human leukemia and lymphoma that is expected to effectively kill cancer cells in mice carrying human T-cell tumors.
Researchers said this therapy is an antibody-drug conjugate (ADC) that combines an antibody targeting the TRBC1 protein expressed on the surface of T cells with the anti-cancer drug SG3249. ADCs work by using antibodies to find cancer cells that express TRBC1. These cancer cells then take up ADC, which causes SG3249 to be released and kill the cancer cells. T-cell leukemias and lymphomas affect approximately 100,000 patients worldwide each year. Adult-onset recurrent T-cell cancers often have very limited treatment options, with 5-year survival rates of 7%-38%.
Researcher Dr. Suman Paul said that developing treatments for T-cell leukemias and lymphomas is much more difficult than treating leukemias and lymphomas caused by the immune system's B cells. Effective treatments for B-cell cancers eliminate both cancerous and noncancerous B cells, but patients can survive well without the immune system's B cells that help fight infections. However, if researchers used similar methods to eliminate normal and cancerous T cells, they would leave patients without a functional immune system and face a high risk of death from infection.
The researchers said that not many drugs have been developed in the field of T-cell leukemia and lymphoma research. So they need to develop drugs that target these cancers, but any therapies developed in this area must be cancer-specific and must eliminate cancerous T cells while sparing some normal T cells. T-cell cancers express either TRBC1 or TRBC2, while normal T cells express a mixture of TRBC1 and TRBC2. Therefore, selective targeting of TRBC1 could potentially eliminate TRBC1-expressing normal and cancerous T cells while sparing TRBC2-expressing normal T cells. A recent clinical trial conducted by researchers attempted to use chimeric antigen receptor T-cell (CAR-T cell) therapy to target TRBC1 cancer.
Figure 1. Generation and testing of anti-TRBC1 CAR T cells. (Nichakawade T D, et al. 2024)
These CAR-T cells are a type of T cell genetically engineered to bind to and kill TRBC1 cells, and CAR-T cell therapy is a new type of therapy approved by the FDA to treat a variety of B-cell cancers. However, when CAR-T cell therapy targeting TRBC1 was used in human patients, researchers found that the CAR-T cells may not persist in the patient's body. These persistences may be necessary to effectively kill cancer cells, and researcher Paul and others are very interested in the reasons why. Through research, they found that CAR-T cells targeting TRBC1 may be killed by normal T cells, thus limiting their persistence.
The lack of persistence of CAR-T cells may have led researchers to try targeting TRBC1 with antibody-drug conjugates, using two different formulations of ADCs in mouse models of T-cell cancer. When the treatment formula is injected one at a time, the cancer initially begins to recede, but then returns. When the anti-TRBC1-SG3249 ADC combination was injected, the researchers observed signs of cancer elimination within 7 days, and the cancer eventually went undetected and did not relapse.
The new treatment clears the cancer while retaining half of the remaining normal T cells, which is enough to maintain the body's immune system protection against infectious diseases. "It is very satisfying to successfully eliminate T-cell cancers while retaining normal T cells in preclinical models," said researcher Jiaxin Ge. "We believe this approach has the potential to address unmet needs in oncology, and we are committed to furthering this research."
Researchers believe they can learn a lot from the clinic and are excited to participate in the iterative process of drug discovery. Each therapy has its advantages and disadvantages, but the clinical efficacy of their ADCs brings certain hope to patients' treatment, and it can bring revolutionary therapeutic effects to patients suffering from terrible cancers. The researchers are currently working with an industry partner to conduct early safety and efficacy clinical trials in human patients.
Reference
Nichakawade T D, et al. TRBC1-targeting antibody–drug conjugates for the treatment of T cell cancers. Nature, 2024: 1-8.