WT1 (Wilms tumor 1) is a transcription factor that is overexpressed in many types of solid tumors, including leukemia, mesothelioma, breast cancer, lung cancer, and ovarian cancer. WT1 is an attractive target for cancer therapy because it is expressed in the majority of tumor cells but not in normal tissues, except for low levels in the kidney and testis. Several WT1-targeted therapies have been developed, including vaccines, antibodies, and small molecules.
Vaccines are designed to stimulate the immune system to recognize and attack cancer cells that express WT1. Several WT1 vaccines have been tested in clinical trials, including peptide vaccines, DNA vaccines, and dendritic cell vaccines. Peptide vaccines are short amino acid sequences that mimic the WT1 protein and are presented to the immune system to generate a response against the tumor. DNA vaccines are plasmids that encode the WT1 protein and are injected into the patient to stimulate an immune response. Dendritic cell vaccines are composed of dendritic cells that have been exposed to WT1 protein or peptide fragments and are injected into the patient to activate the immune system.
Clinical trials of WT1 vaccines have shown mixed results. Some studies have reported promising efficacy, while others have shown no benefit. A phase II trial of a peptide vaccine (galinpepimut-S) in patients with acute myeloid leukemia (AML) showed a significant improvement in overall survival compared to historical controls. Another phase II trial of a dendritic cell vaccine (DCWT) in patients with mesothelioma showed a median overall survival of 26.2 months, which was longer than historical controls. However, a phase III trial of a peptide vaccine (WT1 analog peptide vaccine) in patients with pancreatic cancer showed no improvement in overall survival compared to standard of care.
Antibodies are proteins that recognize and bind to specific targets, including WT1. Several WT1-targeting antibodies have been developed, including murine monoclonal antibodies, chimeric antibodies, and humanized antibodies. Antibodies can be used to directly kill tumor cells or to deliver drugs or toxins to the tumor.
Clinical trials of WT1-targeting antibodies have been limited, and the results have been mixed. A phase I trial of a murine monoclonal antibody (Mab406) in patients with solid tumors showed no objective responses. A phase I/II trial of a chimeric antibody (GSK2831781) in patients with AML showed a 20% complete remission rate. A phase I trial of a humanized antibody (HuMab-5B1) in patients with mesothelioma showed no objective responses.
Small molecules are compounds that inhibit the function of WT1 or its downstream targets. Several small molecules have been developed that target WT1, including peptide-based inhibitors, RNA-based inhibitors, and small molecule inhibitors.
Clinical trials of WT1-targeting small molecules have been limited, and the results have been mixed. A phase I trial of a peptide-based inhibitor (YM155) in patients with advanced solid tumors showed limited efficacy, with only one partial response out of 41 patients. A phase I trial of an RNA-based inhibitor (MRX34) in patients with advanced solid tumors showed promising efficacy, with three partial responses and stable disease in 18 out of 47 patients. However, the trial was halted due to severe immune-related adverse events. A phase I trial of a small molecule inhibitor (Kartogenin) in patients with advanced solid tumors showed no objective responses.
In conclusion, WT1-targeted therapies have shown variable efficacy in clinical trials. While some studies have reported promising results, others have shown no benefit. The optimal approach to WT1 targeting may depend on the tumor type and the stage of the disease. Further research is needed to identify patient populations that are most likely to benefit from WT1-targeted therapies and to develop more effective strategies for targeting WT1 in solid tumors.