Diphtheria Toxin to Fight Cancer?

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About Diphtheria

Corynebacterium diphtheria is the type of bacteria that causes the disease diphtheria. Vaccines for Diphtheria are part of the routinely administered series during childhood. The disease has been largely eliminated due to vaccination, but it has the capacity to resurface when vaccination is discontinued, as it did during the collapse of the former Soviet Union. The bacteria makes a toxin -- a protein that can kill living cells.

About Diphtheria Toxin

Diphtheria toxin, when it goes into the whole body systemically, can cause inflammation of the heart muscle, nerve damage, and other systemic toxic effects. A milder form of diphtheria can be restricted to the skin.

In the early 1960s, a group at Harvard conducted experiments on the mechanism of action of the diphtheria toxin, concluding that the toxin inhibited protein synthesis by blocking the transfer of amino acids to a the growing chain of amino acids – building blocks of the protein-to-be. Later, the exact mechanism of action of the toxin was shown, and it’s become a classic model for people who study bacterial toxins.

About B-cell Malignancies

According to the American Cancer Society, B-cell lymphomas make up about 85 percent of non-Hodgkin lymphomas in the United States. Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma, accounting for about 1 out of every 3 cases.

The B-cells are a type of white blood cell. They require certain signals from other cells to grow and survive. Most patients with B-cell malignancies have two typical markers on the outside of the cancer cells, CD22 and CD19, both of which are required for B-cell function. These markers, or trans membrane proteins, are key to efforts to target B-cell malignancies, as described below.

Engineering the Therapy

Looking for a new approach to treat B-cell malignancies that are refractory to treatment, a group of researchers led by Dr. Daniel Vallera has been developing a targeted approach that uses fragments of antibodies.

Using genetic engineering, they made antibodies that bind to CD19 and CD22 on the B-cell cancer cells, but that also have the bacterial diphtheria toxin attached to the antibody. The result is what is known as an immunotoxin, and this one is called DT2219.

Immunotoxins are not entirely new, however they are still being actively researched and developed. To date, most success has been achieved treating blood cancers. Obstacles to successful use of immunotoxins on solid tumors include poor penetration into the tumor and the immune response to the toxin component of the therapy. Once a patient mounts an immune response to the toxin, this limits the number of cycles of therapy that can be received.

Testing the Therapy

So far, DT2219 has been studied in only the earliest type of clinical trial.

In a phase I clinical trial, researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

According to Ana Pamplona, PhD, from Immuno-Oncology News, the team of researchers performed this phase I study, with preliminary data on efficacy of DT2219, in 25 patients with relapsed/refractory B-cell lymphoma or leukemia.

The patients enrolled in the clinical trial had cancer that was no longer responding to chemotherapy:  pre-B acute lymphoblastic leukemia, chronic lymphocytic leukemia, or non-Hodgkin lymphoma. They had received a total of 2 to 5 treatments prior to entering this trial. A total of 8 patients had received previous unsuccessful bone marrow transplants. All tumors were positive for CD19 and/or CD22, and patients were treated with a single cycle of increasing doses of the immunotoxin therapy.

Guarded Optimism

There were some promising signs with DT2219. However, since this was a Phase I study, the primary objective was to find a dose range that produced positive results while identifying side effects.

DT2219 was administered intravenously during 2 hours every 2 days in a total of 4 doses.

  • The drug completely eliminated the cancer in one of their patients.
  • Two of 10 patients in one subset had long-lasting responses.

Patients making antibodies to the toxin is an obstacle with this kind of therapy, since the immune response to the toxin can result in drug rejection. In this study, this rejection occured in 30 percent, but the group is working toward a version of the toxin that would be less likely to cause this kind of reaction.

Sources

Phase I Study of a Bispecific Ligand-Directed Toxin Targeting CD22 and CD19 (DT2219) for Refractory B-cell Malignancies http://clincancerres.aacrjournals.org/content/21/6/1267.abstract Accessed March 2015

Modified Immunotoxin as Potential Therapy for Patients With B-cell Malignancies. http://immuno-oncologynews.com/2015/03/17/modified-immunotoxin-as-potential-therapy-for-patients-with-b-cell-malignancies/ Accessed March 2015.

Todar’s Online Textbook of Bacteriology. http://textbookofbacteriology.net/diphtheria.html Accessed March 2015.

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