WT1 is a protein that is often present on the surface of pleural mesothelioma cells. After clinical trials found that galinpepimut-S (GPS), a WT1-specific vaccine, is safe and effective in causing programmed death in other malignancies where WT1 is present, researchers investigated the impact of combining GPS with nivolumab immunotherapy in previously treated mesothelioma. Preliminary results found that the combined administration induced immune responses and that pleural mesothelioma patients may derive a benefit from the new treatment.
What Is the WT1 Protein?
The WT1 protein (Wilm’s tumor protein 1) is a protein that plays a key role in the development of the kidneys in fetal life, then disappears from normal organs and tissues. In roughly 20 types of cancer, it returns in at least 50% of tumor pathology specimens and is present in large amounts in certain malignancies, including malignant mesothelioma.[1]
Because it is highly expressed in several types of hematological malignancies and solid tumors, it has been identified as a promising target for immunotherapy — in fact, in 2009, the National Cancer Institute (NCI) conducted a prioritization study that ranked 75 tumor-associated antigens to determine which held the most promise based on therapeutic function, immunogenicity, and several other factors, and WT1 was at the top of the list.[2]
Based on this, researchers reviewed all published cancer vaccine trials reporting on WT1-targeted active specific immunotherapy in patients with hematological malignancies and solid tumors to assess their potential for creating clinical responses. They found that most studies showed some benefit for a significant number of patients and that WT 1-based cancer vaccines were both feasible and safe in patients with multiple tumor types.[3]
What is Galinpepimut-S?
Galinpepimut-S (GPS) is a WT1-targeting cancer immunotherapeutic licensed by Sellas Life Sciences Group from Memorial Sloan Kettering Cancer Center. It is being developed as both a single therapy and a combination therapy for different types of cancers.[1]
GPS contains four peptides, two of which have been deliberately mutated into a substance that elicits a strong T-cell response in cancer cells. The product is being tested to see whether it can target tumors that have an overexpression of WT1 to counter their notable lack of T cells reactive to WT1. The developers hope that the immune response generated by GPS will lead to the body’s immune system attacking and killing WT1-positive cancer cells and that it will eventually establish immunologic memory against WT1-expressing cancers.[1]
What Is Galinpepimut Used For?
The Wilms Tumor 1 (WT1) protein is present and over-expressed in several hematological malignancies and solid tumors, and galinpepimut has been designed to target this antigen. Used as either a monotreatment or in combination with other immunotherapy, GPS may provide a highly effective way to delay or prevent relapse or recurrence in patients in complete remission or with minimal residual disease.[4]
To date, GPS has been tested alone and in combination with PD-1 inhibitors and has shown positive responses in several cancers, including:
- Acute Myeloid Leukemia
- Malignant Pleural Mesothelioma
- Multiple Myeloma
- Ovarian Cancer
In 2024, Galinpepimut received orphan drug designation from the U.S. Food and Drug Administration for the treatment of pediatric acute myeloid leukemia.
Can Galinpepimut be Used to Treat Mesothelioma?
Because malignant pleural mesothelioma has been identified as a solid tumor that has high levels of expression of WT1, multiple studies of the use of galinpepimut have been conducted or are in the process of being administered. These include:
- A 41-patient Phase 2, double-blind, randomized study was performed at Memorial Sloan Kettering Cancer Center and MD Anderson Cancer Center and was co-sponsored by the Department of Defense. The study revealed that the treatment had a well-tolerated safety profile and provided a median overall survival of 22.8 months as compared to 18.3 months in the control group.[4]
- Researchers from the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center combined GPS with nivolumab in a single-center Phase 1 study to examine tolerability and immunogenicity in patients with previously treated diffuse pleural mesothelioma. All participants had previously been treated with at least one course of pemetrexed-based chemotherapy.[5]
Patients received two doses of GPS followed by six doses of GPDS with intravenous nivolumab every two weeks, and up to six additional cycles until their disease progressed or toxicity became unacceptable. Of the ten patients treated, 7 experienced mild treatment-related adverse events and two experienced a grade 3 or higher adverse event. Three reported vaccine-specific T-cell responses and there were no partial responses. Three patients remained stable with decreases in tumor volume, and the median progression-free survival was 3.9 months, median overall survival was 7.4 months.[5]
Potential Adverse Events of Galinpepimut-S
Any treatment has inherent risks, and this is particularly true of those that are just beginning to be tested. Though the most obvious risk is that the treatment won’t work, identifying clinical adverse effects is one of the primary goals of any treatment research. In testing the safety and tolerability of Galinpepimut-S in combination with nivolumab, researchers identified several adverse events. The most common of these was fatigue and infusion-related reactions as well as skin induration. The most serious toxicities attributed to the study intervention were atrial fibrillation and an infusion-related reaction during the administration of nivolumab. Other treatment-related adverse events included:
- Anorexia
- Constipation
- Dizziness
- Injection site reaction
- Lung infection
- Pelvic pain
- Pneumonitis
Future Testing of Galinpepimut-S Vaccine for Mesothelioma
To date, clinical trials testing Galinpepimut-S as a vaccine for mesothelioma have shown increased survival as maintenance therapy. Two recent studies showed improved survival in active disease when combined with checkpoint blockade drugs in malignant pleural mesothelioma. The drug’s developers believe that these findings confirm the strong biological effect of galinpepimut-S, even in challenging disease settings.
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