A collaborative effort between Dana-Farber Cancer Institute, Washington University School of Medicine, MD Anderson Cancer center, Houston, TX, Seattle Genetics, Inc, Bothel, WA and other institutions, have developed a toxin linked to a monoclonal antibody that demonstrates anti-tumor activity in patients who have non-Hodgkin lymphomas that were no longer responding to therapy. This is an ongoing open-label Phase 2 study. The study was designed to test the activity of brentuximab vedotin (Adcetris) in relapsed or refractory non-Hodgkin lymphoma (NHL) including B-cell cancers such as diffuse large B cell lymphoma (DLBCL).
According to Jacobsen, MD, of Dana-Farber and senior author of the study, the new antibody-toxin compound is approved for therapy on relapsed or refractory Hodgkin lymphoma and anaplastic T cell lymphoma. The success of the new compound has prompted the trial in NHL. First author is Nancy Bartlett, MD, of Washington University School of Medicine.
So far, the trial has enrolled 62 patients with B-cell lymphomas. This includes 44 patients diagnosed with DLBCL. According to researchers, the majority of patients were no longer responding to previous treatments. And, 23 percent of these patients had never responded to any therapy.
Of the 43 evaluable DLBCL patients, 40 percent had an objective response to the compound with a median duration of 36 weeks, including some of more than 8 months. Seven patients had complete remissions and 10 had partial. In the other B-cell lymphoma patients, 22 had an objective response (primary end point).
Jacobsen notes, “It was more active than many expected. In my opinion, these results are encouraging enough to take the drug forward in diffuse large B cell lymphoma”.
The antibody-drug conjugate, brentuximab, binds to a molecule known as CD30 on cells in Hodgkin lymphoma and anaplastic T cell lymphoma. CD30 expression varies in subtypes of lymphoma, however is estimated to be present in one-quarter to one-third of B cell NHL cells. This conjugate interferes with cell growth and division. The antibody-drug conjugate is taken in by cancer cells that carry CD30 on their surface. Once the conjugate is inside the cancer cell, brentuximab separates from the antibody and disables the cell.
The expression of the CD30 molecule varies in patients with lymphoma. Some patients expressed it strongly, other less and some not all. Jacobsen notes, the strength of CD30 expression had no relationship to how the patient responded to brentuximab. “In fact, although the trend was not statistically significant, there was almost an inverse correlation. Some patients with the weakest CD30 expression had the most positive responses.”
Jacobsen goes on to say, he is puzzled. How did the antibody bind to lymphoma cells that lacked the CD30 molecule? One possibility is that it is binding to another target, however preclinicals suggested this was not the case. Other possibilities include; brentuximab vedotin binds more effectively to CD30 than the antibody used to detect CD30 or different cells have differing abilities to ingest brentuximab once the antibody binds to the cell. At the moment, there is no clear answer. Further lab test are needed and on going. At this point, the trial is evaluating brentuximab’s activity in a cohort of patients whose lymphomas have no measurable CD30 expression.
The researchers report that brentuximab caused a number of adverse events that lead to discontinuation of 6 patients. The adverse events include fatigue, nausea, low white blood counts, fever, diarrhea, peripheral sensory neuropathy, vomiting, anemia and constipation.
Photo from www.thirdage.com