WT1 Peptide Vaccine for Leukemia
Peptide Cancer Vaccines
21 month median OS
In the phase 2 trial of galinpepimut-S, AML patients in first complete remission achieved a median overall survival of 21 months, compared to 5.4 months for historical controls.
Maslak et al., Blood Advances, 2018
Maslak et al., Blood Advances, 2018
View as imageThe National Cancer Institute convened a panel to rank cancer antigens by their suitability for immunotherapy. WT1 (Wilms' tumor 1) came out on top. The protein is overexpressed in the majority of acute myeloid leukemia (AML) cases, in myelodysplastic syndromes (MDS), and across a range of solid tumors including mesothelioma, ovarian, and lung cancer. It sits on the surface of cancer cells in a form that T cells can recognize, it drives tumor growth when present, and healthy tissues express it at low enough levels that immune attack can be selective.[1] These properties make WT1 the most extensively tested target for peptide-based cancer vaccines. For an overview of how personalized cancer vaccines work at the neoantigen level, see the pillar article. This piece focuses specifically on WT1 peptide vaccines in leukemia: what the clinical trials show, where galinpepimut-S stands, and what gaps remain.
Key Takeaways
- WT1 is overexpressed in 75-90% of AML cases, making it a near-universal target for this cancer (Oka et al., Current Med Chem, 2006)
- Galinpepimut-S, a multivalent WT1 peptide vaccine, produced median overall survival of 21 months in AML patients in first remission, vs 5.4 months historical (Maslak et al., Blood Advances, 2018)
- A review of 9 WT1 vaccination studies found measurable immune responses and clinical benefit across AML and MDS patients (Di Stasi et al., Frontiers in Immunology, 2015)
- The phase 3 REGAL trial passed its interim futility analysis in 2025, with 80% of GPS-treated patients showing T-cell immune responses
- Combining WT1 killer and helper peptides generates stronger, more persistent cytotoxic T lymphocyte responses than killer peptides alone (Fujiki et al., 2021)
- A novel WT1 peptide target bypassed immunoproteasome dependency, potentially reaching tumors that escape standard WT1 vaccines (Lahman et al., Science Translational Medicine, 2022)
What WT1 is and why cancer cells overexpress it
WT1 encodes a zinc-finger transcription factor originally identified as a tumor suppressor in Wilms' tumor, a childhood kidney cancer. The relationship between WT1 and cancer turned out to be more complex than the name suggests. In most adult cancers, WT1 functions as an oncogene: it promotes cell proliferation, inhibits apoptosis, and supports angiogenesis. When researchers measured WT1 expression across cancers, they found it was overexpressed in 75-90% of AML cases, the majority of MDS cases, and many solid tumors.[1]
This overexpression creates the therapeutic opportunity. Fragments of the WT1 protein are processed by the proteasome inside cancer cells and presented on the cell surface bound to MHC class I molecules. These peptide-MHC complexes act as flags that cytotoxic T cells (CD8+ T cells) can recognize and use to identify and kill the cancer cell. The strategy behind WT1 peptide vaccines is straightforward: inject a patient with synthetic WT1 peptide fragments to prime and expand T cells that recognize WT1-expressing cancer cells.
What makes WT1 particularly attractive compared to other cancer antigens is its expression pattern. In healthy adult tissues, WT1 is expressed at low levels primarily in podocytes (kidney cells), Sertoli cells (testes), and some CD34+ bone marrow progenitors. Cancer cells express it at 10-1000 times higher levels. This differential expression provides a therapeutic window: enough expression on tumor cells for immune recognition, low enough expression on normal cells to avoid severe autoimmunity.
Two decades of clinical evidence
The foundational studies
Oka and colleagues published the development rationale for WT1 peptide vaccines in 2006, establishing the preclinical and early clinical framework for targeting WT1 in both hematopoietic malignancies and solid cancers.[1] The earliest clinical observations were striking: in some patients, a single dose of WT1 peptide vaccination produced an increase in WT1-specific cytotoxic T lymphocytes, followed by measurable reductions in leukemic blast cells.
The nine-study review
Di Stasi and colleagues published a systematic review in 2015 that aggregated results from nine different WT1 peptide vaccination studies in AML and MDS.[2] Across these studies, WT1 peptide vaccines consistently produced measurable immune responses (expansion of WT1-specific T cells) and clinical responses ranging from reduced WT1 transcript levels to sustained remissions. The heterogeneity of vaccine formulations, dosing schedules, and patient populations made it difficult to draw definitive efficacy conclusions, but the consistent signal across nine independent studies built a strong case for advancing to larger trials.
Pilot trial with synthetic analog peptides
Brayer and colleagues tested WT1 vaccination using synthetic analog peptides (modified versions designed to enhance immunogenicity) in AML and MDS patients in 2015.[3] The analog approach substitutes specific amino acids to increase binding to MHC molecules and enhance T cell recognition, while preserving the T cell's ability to cross-react with the natural WT1 peptide on tumor cells. This study demonstrated that heteroclitic (modified) peptides could induce more robust immune responses than native WT1 peptides.
Galinpepimut-S: the leading WT1 vaccine candidate
Galinpepimut-S (GPS) is a multivalent WT1 peptide vaccine developed by SELLAS Life Sciences. Unlike earlier single-peptide WT1 vaccines, GPS contains four peptide antigens: two native WT1 peptides and two heteroclitic analogs, targeting both HLA class I (CD8+ T cell) and HLA class II (CD4+ T helper cell) responses. This multivalent design addresses a limitation of earlier WT1 vaccines that focused only on killer T cell (CD8+) epitopes.
Phase 2 results in AML
Maslak and colleagues published the phase 2 trial of GPS in AML patients in 2018.[4] The trial enrolled patients in first complete remission (CR1) who received GPS as maintenance therapy. Key findings:
- Median overall survival from CR1: 21 months for GPS-treated patients
- Historical comparison: approximately 5.4 months median OS for similar patients receiving standard of care
- The vaccine was well tolerated, with the most common adverse events being grade 1/2 injection site reactions (46%), fatigue (32%), and skin induration (32%)
- No grade 4 or 5 treatment-related adverse events
The survival improvement is notable, but the comparison to historical controls rather than a randomized placebo arm limits the strength of the evidence. Patients who achieve CR1 and are well enough for maintenance therapy may have better prognosis regardless of treatment.
The REGAL phase 3 trial
The REGAL trial (NCT04229979) is a randomized, open-label phase 3 study comparing GPS to best available therapy as maintenance in AML patients in second complete remission (CR2) or second complete remission with incomplete hematologic recovery (CRp2). This is a higher-risk population than the phase 2 trial, with a historical median overall survival of approximately 6 months.
As of early 2026, the trial has passed its prespecified interim futility analysis. The Independent Data Monitoring Committee recommended the trial continue without modifications after reviewing data at 60 events (deaths). Key interim findings:
- After a median follow-up of 13.5 months, fewer than 50% of enrolled patients had died
- 80% of randomly selected GPS-treated patients showed specific T-cell immune responses to WT1
- No safety concerns were identified
The final analysis, triggered at 80 events, was expected by late 2025 or early 2026. Results have not been publicly released as of March 2026. If REGAL meets its primary endpoint (overall survival superiority over best available therapy), GPS would become the first peptide-based cancer vaccine to demonstrate efficacy in a randomized phase 3 trial for a hematologic malignancy.
Advancing the science: helper peptides and alternative epitopes
Killer + helper peptide combinations
Early WT1 vaccines targeted only MHC class I epitopes, activating CD8+ killer T cells. Fujiki and colleagues demonstrated in 2021 that co-vaccination with both WT1 killer and helper peptides (targeting CD4+ T cells) generated stronger and more persistent cytotoxic T lymphocyte responses.[5] The study identified a novel population of WT1-tetramer-high, CD5-high CTLs that appeared only in patients receiving the combination. This population showed enhanced persistence, suggesting that CD4+ T cell help is critical for maintaining long-term anti-tumor immunity.
This finding informed the design of GPS (which includes class II peptides) and the cocktail vaccine tested by Tsuboi and colleagues in 2019 for recurrent malignant glioma, which combined HLA class I and class II WT1 peptides and showed safety across all dose levels.[6]
Bypassing immunoproteasome dependency
A challenge with WT1 peptide vaccines is that the standard WT1 epitope (WT1 126-134) requires processing by the immunoproteasome, a variant of the proteasome that is upregulated during immune activation. Some tumor cells downregulate the immunoproteasome as an immune evasion strategy, making them invisible to T cells primed against the standard epitope.
Lahman and colleagues addressed this in 2022 by identifying an alternate WT1 peptide (WT1 37-45) that is processed by the constitutive proteasome instead.[7] A TCR (TTCR37-45) targeting this alternate epitope effectively killed relapsed AML cells that were resistant to standard WT1 targeting. This approach provides a potential strategy for patients whose leukemia escapes standard WT1 vaccines through immunoproteasome downregulation.
Beyond leukemia: WT1 vaccines in solid tumors
WT1 overexpression extends well beyond leukemia. Ogasawara and colleagues reviewed the full landscape of WT1-targeting cancer vaccines in 2024, documenting clinical trials across AML, MDS, glioma, mesothelioma, ovarian cancer, and pancreatic cancer.[8]
Koido and colleagues reported in 2025 on a dendritic cell vaccine pulsed with WT1 peptide cocktails in advanced pancreatic cancer, with some patients achieving conversion to surgical candidates through combined chemoimmunotherapy.[9] The pancreatic cancer application is particularly notable because this cancer type has been resistant to most immunotherapy approaches.
For readers interested in how peptide vaccines are combined with other immunotherapies, the article on peptide vaccines and checkpoint inhibitors covers this emerging strategy. The combination of WT1 peptide vaccination with checkpoint blockade (anti-PD-1 or anti-PD-L1) is being investigated as a way to amplify the vaccine-induced T cell response by removing the brakes that tumors apply to the immune system.
What the evidence does not yet prove
Despite two decades of clinical work, several questions remain open.
No completed phase 3 randomized data. The REGAL trial is ongoing and has not reported final results. All prior evidence comes from phase 1/2 trials and historical comparisons. The history of cancer vaccines includes multiple candidates that showed promise in early trials but failed in phase 3.
Patient selection remains unclear. Which AML patients benefit most from WT1 vaccination is not well defined. WT1 expression levels vary across patients, HLA type restricts which epitopes can be presented, and immune fitness after chemotherapy differs. Biomarkers to predict vaccine response are not validated.
Duration of immunity. Some reports describe WT1-specific T cell responses persisting for up to 10 years after vaccination, but these are individual case reports, not population-level data. Whether the vaccine can maintain remission long-term in most patients is unknown.
Comparison to other immunotherapies. In AML, allogeneic stem cell transplant remains the standard consolidation approach for eligible patients. How WT1 vaccination compares to or complements transplant has not been tested in a randomized trial. Similarly, the relative benefit of WT1 peptide vaccines versus bispecific T cell engagers or CAR-T cells targeting WT1 is unexplored.
Solid tumor efficacy is less mature. While WT1 vaccines have shown immune responses in solid tumors, clinical responses are less consistent than in hematopoietic malignancies. Solid tumors present additional barriers (immunosuppressive microenvironment, poor T cell infiltration) that may limit peptide vaccine efficacy without combination approaches.
Links to related articles in this cluster: gp100 peptide vaccine for melanoma, HER2 peptide vaccines for breast cancer, KRAS peptide vaccines, and multi-epitope peptide vaccines.
The Bottom Line
WT1, ranked the top cancer antigen by an NIH panel, is overexpressed in 75-90% of AML cases and is the most extensively tested target for peptide cancer vaccines. Galinpepimut-S (GPS), a multivalent WT1 vaccine containing both killer and helper peptides, produced a median overall survival of 21 months in phase 2 AML maintenance therapy and is currently in a phase 3 trial (REGAL) that passed its interim futility analysis in 2025. Advances in vaccine design include combination killer/helper peptide approaches that generate more persistent T cell responses and alternate epitopes that bypass immunoproteasome-dependent processing. Randomized phase 3 data is expected but not yet available, and the translation to solid tumors remains in earlier stages.