Tremelimumab, formerly ticilimumab, is a fully human IgG2 monoclonal antibody produced by Pfizer, undergoing human trials for the treatment of cancer.Cytotoxic T lymphocytes (CTLs) can recognize and destroy cancer cells. However, there is also an inhibitory mechanism that interrupts this destruction. Tremelimumab turns off this inhibitory mechanism and allows CTLs to continue to destroy the cancer cells.

Tremelimumab binds to the protein CTLA-4, which is expressed on the surface of activated T lymphocytes and inhibits the killing of cancer cells. Tremelimumab blocks the binding of the antigen-presenting cell ligands B7.1 and B7.2 to CTLA-4, resulting in inhibition of B7-CTLA-4-mediated down-regulation of T-cell activation; subsequently, B7.1 or B7.2 may interact with another T-cell surface receptor protein, CD28, resulting in a B7-CD28-mediated T-cell activation unopposed by B7-CTLA-4-mediated inhibition.Tremelimumab stimulates patients’ immune systems to attack their tumors. It has induced durable tumor responses in patients with metastatic melanoma in Phase 1 and Phase 2 clinical studies.On April 2, 2008, Pfizer announced that it has discontinued a Phase III clinical trial for patients with advanced melanoma after the review of interim data showed that the trial would not demonstrate superiority to standard chemotherapy.

Recently, pretreatment peripheral blood samples from 218 patients with melanoma who were refractory to prior therapy and receiving tremelimumab in a multicenter phase II study were measured for 169 mRNA transcripts using reverse transcription polymerase chain reaction (RT-PCR).A two-class latent model yielded a risk score based on four genes that were highly predictive of survival(P < 0.001). This signature was validated in an independent population of 260 treatment-naive patients with melanoma enrolled in a multicenter phase III study of tremelimumab.

Results have showed that expression levels of the 169 genes were closely correlated across the two populations. A four-gene model, including cathepsin D(CTSD), phopholipase A2 group VII (PLA2G7), thioredoxin reductase 1(TXNRD1), and interleukin 1 receptor–associated kinase 3 (IRAK3), predicted survival in the test population. Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral blood are predictive of survival in patients with melanoma treated with tremelimumab. Blood mRNA signatures should be further explored to define patient subsets likely to benefit from immunotherapy.

Reference:

Blood mRNA Expression Profiling Predicts Survival in Patients Treated with Tremelimumab. Clinical Cancer Research. 2014;1-9.