New Therapeutic Approaches for Malignant Mesothelioma Using Immunotherapy to Target WT1

Immunotherapy targeting WT1 may help patients with malignant mesothelioma.by Tao Dao, Lee M. Krug and David A. Scheinberg, Memorial Sloan Kettering Cancer Center, New York, NY

Wilms’ tumor  1 (WT1) is a protein that is present at high levels in many types of cancers (especially mesothelioma), but it is generally not found in normal cells. Therefore, we think that it is a potential target for novel therapies, and particularly immunotherapies. WT1 is typically found inside the cell, in the nucleus. Only after it is processed and moved to the surface of the cancer is it possible for the immune system to see it. We think that if we could teach the immune system to attack WT1, we could find an effective way to specifically kill mesothelioma cancer cells.

At Memorial Sloan Kettering Cancer Center, we are studying two ways to boost the immune response against WT1. The first is with a vaccine. Normally, the WT1 protein does not cause an immune response to occur. However, we found that small pieces of WT1 proteins that are just slightly different from normal WT1 protein can stimulate the immune system better. If we can teach the patient’s immune system to target WT1 using a vaccine made up of these protein pieces, then perhaps it will also learn to attack the cancer cells. In fact, when we gave the WT1 vaccine to patients along with some immune booster medicines, they developed an excellent immune response specifically to WT1. We are now studying this vaccine in a larger clinical trial to see if it is effective against the cancer. Patients who have undergone surgery for mesothelioma either get the immune boosters alone or together with the WT1 vaccine to see if it can prolong the time before the mesothelioma grows back.

We are now also studying another way to attack WT1 using antibodies. Antibodies are proteins in the body that stick to foreign substances (such as bacteria or viruses) and tag them for destruction by the immune system. In this case, however, we have engineered antibodies in a laboratory so they will recognize WT1. Thus, instead of the vaccine strategy which relies on teaching the patient’s immune system to attack WT1, these antibodies can be injected and bind directly to it. We have demonstrated that this antibody is a potent therapeutic agent against human mesothelioma in animal models. Our study was published in the Science Translational Medicine in March, 2013. (http://stm.sciencemag.org/content/5/176/176ra33.long). We are working to bring this promising new drug to clinical application in the very near future.

Acknowledgement

We greatly appreciate the grant support from the Mesothelioma Applied Research Foundation for our exciting research targeting WT1 by both vaccines and antibody therapies (TD and LMK are recipients of Meso Foundation grants).

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