Genetically engineered immunotoxin shows early promise in patients with B-cell malignancies
American Association for Cancer Research
Public Release: 13-Mar-2015
Almost all patients with a group of blood cancers called B-cell malignancies have two prominent "fingerprints" on the surface of leukemia and lymphoma cancers, called CD22 and CD19, Vallera explained. To develop the drug, Vallera and colleagues chose two antibody fragments that each selectively bind to CD19 and CD22. They used genetic engineering to attach these two antibodies to a potent toxin, the bacterial diphtheria toxin. When the antibody fragments bind to the two targets on the cancer cell, the entire drug enters the cell, and the toxin kills the cell.
Vallera; Veronika Bachanova, MD, PhD, oncologist and an assistant professor at the University of Minnesota; and colleagues enrolled 25 patients to the trial. Patients had chemo-refractory pre-B acute lymphoblastic leukemia, chronic lymphocytic leukemia, or non-Hodgkin lymphoma, and had received two to five prior therapies, with eight of them having had previous unsuccessful bone marrow transplantations. All tumors were confirmed to have CD19 and/or CD22 proteins. In this dose-escalation study, all patients received a single cycle of varying doses of the immunotoxin therapy.
Two of the 10 evaluable patients had durable objective responses. One of them had a complete remission after receiving two cycles of treatment. The maximum tolerated dose was not reached but clinical responses occurred between doses 40 to 80 µg/kg administered in four infusions.
In an interview, Vallera said, "In this phase I trial, we found a safe dose of the drug that has biological activity. Of the 10 evaluable patients, two of them responded. We are planning a phase II trial with this drug. It will focus on giving more cycles of treatment, which we believe will dramatically enhance the response rates. We were surprised that the drug was effective enough to entirely eliminate the cancer in one of our patients. Further, we expected the patients to make antibodies against the bacterial toxin and thus reject our drug. Surprisingly, this did not occur in the majority of our patients [70 percent]. We need to study more patients to understand why they did not produce neutralizing antibodies. However, we also have been working to create a less immunogenic form of the toxin for the next-generation drug."
Vallera added, "Another important fact about our drug is that it was home-grown, meaning there was no commercial partner, which is rare. The drug was funded mostly with private donations including individuals that have lost loved ones to cancer."
Bottom Line: DT2219, a new bispecific ligand-directed diphtheria toxin, was found to be safe and clinically effective in a small group of patients with relapsed/refractory B-cell malignancies, according to phase I clinical trial data.
Journal in Which the Study was Published: Clinical Cancer Research, a journal of the American Association for Cancer Research
Author: Daniel Vallera, PhD, professor of radiation oncology and director of the section on molecular cancer therapeutics at Masonic Cancer Center in the University of Minnesota in Minneapolis
Funding & Disclosures: This study was supported by the National Institutes of Health, the Randy Shaver Foundation, the Lions Children's Cancer Fund, and the William Lawrence and Blanche Hughes Foundation. Vallera declares no conflicts of interest.
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