WT1 Peptide Vaccination For Patients Research Articles

Review of the Results of WT1 Peptide Vaccination Strategies for Myelodysplastic Syndromes and Acute Myeloid Leukemia from Nine Different Studies.

We performed a systematic review of data from nine clinical trials of WT1 peptide vaccination in patients with myelodysplastic syndromes and/or acute myeloid leukemia (MDS/AML), published between 2004 and 2012. A total of 51 patients were eligible for analysis. Vaccination with WT1 peptides proved safe and feasible in patients with MDS/AML, in studies from different institutions. Additionally, clinical responses and clinical benefit were observed, with some patients achieving and maintaining remission long-term (more than 8 years). A significant correlation between induction of WT1-specific T cells and normalization/reduction of WT1 mRNA levels and progression-free survival was noted in a number of studies. However, larger studies are warranted to confirm these results. Interestingly, the majority of trials reported the presence of WT1-specific T cells with limited or absent functionality prior to vaccination, which increased in frequency and function after vaccination. In conclusion, WT1 peptide vaccination strategies were safe in this heterogeneous group of patient with MDS/AML. Larger and more homogeneous studies or randomized clinical trials are needed to quantify the contribution of WT1 peptide vaccines to clinical responses and long-term survival.

Long-term WT1 peptide vaccination for patients with acute myeloid leukemia with minimal residual disease

Long-term WT1 peptide vaccination for patients with acute myeloid leukemia with minimal residual disease

Clinical effects of Wilms tumor protein (WT) 1 peptide vaccination in patients with WT1-expressing solid tumors as compared to patients with AML/MDS.

2560 Background: WT1 holds great promise for cancer immunotherapy, is expressed in many hematologic and solid malignancies, and is essential for tumor proliferation. After demonstrating good immunological and clinical efficacy of WT1 peptide vaccination in patients with active AML and MDS, we have initiated a vaccination trial for patients with WT1 expressing carcinomas. We here compare immunogenicity and clinical efficacy among carcinoma patients (CP) and AML/MDS patients. Methods: Patients with ovarian (n=8), thyroid (n=2), breast (n=1), gastric (n=1), and larynx cancer (n=1), astrocytoma (n=1) and mesothelioma (n=3) received 0.2mg HLA-A0201-restricted WT1.126-134 peptide admixed with 1 mg KLH (day 3), and 62.5µg GM-CSF (day 1-4). Quantitation of WT1 specific T cells was performed in peripheral blood (PB) of CP by tetramer staining and compared with analogue analyses in 25 AML/MDS patients. Results: Seventeen CP received a median of 11 vaccinations (range 1-35) and 12 of 17 are evaluable for T cell response. None of the 12 had WT1-specific T cells at baseline, in contrast to 28% of AML/MDS patients. After 4 vaccinations WT1-specific T cells were detectable in 67% of CP and in 54% of AML/MDS patients. After 6 vaccinations WT1-specific T cells were present in 40% of CP and in 78% of AML/MDS patients. Thus, the overall conversion rate was 75% in CP and 56% in AML/MDS. WT1 specific CD8+ T cells in most AML/MDS patients remained detectable during the course of vaccination, whereas in CP WT1 specific CD8+ T cells were only transient, despite of continuation of vaccination and ongoing clinical efficacy, which was demonstrated with 1 partial remission and 6 disease stabilisations between 2 and 22+ months. Conclusions: These results demonstrate profound differences in spontaneous and vaccine induced T cell response among patients with haematological and solid malignancies, suggesting considerably higher spontaneous immunogenicity of AML/MDS, but a higher conversion rate in CP. In contrast to AML/MDS WT1 specific T cells in PB of CP were despite ongoing clinical efficacy only transient, possibly due to migration into the tumor.

Clinical efficacy of WT1 peptide vaccination in patients with acute myelogenous leukemia and myelodysplastic syndrome

Clinical efficacy of WT1 peptide vaccination in patients with acute myelogenous leukemia and myelodysplastic syndrome

Leukemia-associated antigen-specific T-cell responses following combined PR1 and WT1 peptide vaccination in patients with myeloid malignancies

We describe the safety and immunogenicity of a combined vaccine of 2 leukemia-associated antigenic peptides, PR1 and WT1. Eight patients with myeloid malignancies received one subcutaneous dose each of PR1 and WT1 vaccines in Montanide adjuvant, with granulocyte-macrophage colony-stimulating factor. Patients were reviewed weekly for 4 weeks to monitor toxicity and immunologic responses. Toxicity was limited to grades 1 to 2. Using peptide/HLA-A 0201 tetramers and intracellular interferon-gamma staining, CD8(+) T cells against PR1 or WT1 were detected in 8 of 8 patients after a single vaccination. To monitor the kinetics of vaccine-induced CD8(+) T-cell responses and disease regression after vaccination, absolute PR1 and WT1(+)CD8(+) T-cell numbers and WT1 expression were studied weekly after vaccination. Responses occurred as early as 1 week after vaccination. After vaccination, the emergence of PR1 or WT1(+)CD8(+) T cells was associated with a decrease in WT1 mRNA expression as a marker of minimal residual disease, suggesting a vaccine-driven antileukemia effect. Conversely, loss of response was associated with reappearance of WT1 transcripts (P < .01). This is the first demonstration that a combined PR1 and WT1 vaccine is immunogenic. These results support further studies of combination immunization strategies in leukemia patients.

Clinical and Immunological Activity of WT1 Peptide Vaccination in Patients with Acute Myeloid Leukemia and Myelodysplasia: Results of a Phase II Trial.

The transcription factor Wilms tumor protein (WT) 1 belongs to a new generation of tumor antigens, which are essential for tumor cell proliferation. WT1 is highly expressed in AML and in MDS upon appearance of blasts. A phase II trial of vaccination with the HLA-A2-restricted WT1.126–134 peptide was performed in patients with AML and MDS and overexpression of WT1 to determine immunogenicity and clinical activity. Patients received vaccinations with 0.2 mg WT1.126–134 peptide (day 3), 62.5 mcg dendritic cell-stimulating adjuvant GM-CSF (days 1–4) and 1 mg T helper protein keyhole limpet hemocyanin (day 3). The initial 13 patients were to receive 4 biweekly and subsequent 4-weekly vaccinations, the subsequent 13 patients were continuously vaccinated biweekly. Vaccination was continued in absence of overt disease progression. WT1 levels were assessed by quantitative RT-PCR and WT1-specific T cell responses by tetramer analyses and cytokine flow cytometry. Response assessment following IWG-MDS criteria was used, capturing stable disease and hematologic improvement. A duration of 8 weeks was required for stable disease. Enrolment was completed in June 2006 with 24 patients with AML and 2 with MDS (RAEB). Of the 24 AML patients, 16 had > 5% marrow blasts at study onset (8 without prior chemotherapy, 4 with disease persistence following chemotherapy, 4 with PR), and 8 were in CR at high risk for relapse. A median of 10 (range 4 – 23) vaccinations was administered with 8 patients currently still under treatment. No significant toxicity occurred. To date, 22 patients are evaluable for clinical response. Overall, 8/16 patients with > 5% marrow blasts at study onset displayed clinical efficacy of vaccine treatment (SD or better). One AML patient achieved CR for 12 months after brief initial progression, and 7 patients had disease stabilization (2, 2+, 3, 3, 6, 10+, 14 months). One of these patients with RAEBII had a major response of neutrophils and platelets, and one AML patient had initial progression and subsequent transient complete clearance of peripheral blasts. WT1 transcripts as molecular disease marker decreased at least 3-fold (range 3-fold - >50-fold, median >10-fold) in 12 of 20 currently evaluated patients, including all 8 patients with evidence of clinical efficacy and 4 of 5 AML patients vaccinated in CR. The generation of a WT1-specific T cell response in peripheral blood and bone marrow was detected in 12 of 16 evaluated patients including all 6 of these 16 patients with evidence for clinical efficacy. This study shows that WT1 vaccination has promising antileukemia activity. A multicenter comparative WT1 vaccination study in CR patients at high risk of relapse is currently initiated.

Clinical and immune responses of WT1-peptide vaccination in patients with acute myeloid leukemia

2511 Background: The transcription factor Wilms tumor protein (WT) 1 belongs to a new generation of tumor antigens, as it is essential for tumor cell proliferation. WT1 is highly expressed both in myeloid leukemias and many carcinomas. This phase 2 proof-of-concept trial was initiated to determine immunogenicity and toxicity of vaccination with a novel HLA-A2-restricted WT1 peptide vaccine. Methods: Sixteen HLA-A2-positive patients with acute myeloid leukemia and one patient with myelodysplasia received 3–18 vaccinations (median 8) of WT1. 126–134 peptide (0.2 mg) together with the T helper protein keyhole limpet hemocyanin (1 mg) and in addition GM-CSF (75 mcg for four days) and. Twelve patients had elevated blast counts at study entry and 5 patients complete remission with high risk for relapse. Results: Six of 12 patients with presence of leukemic blasts had evidence of antileukemic activity. One patient achieved complete remission for 12 months. The patient with myelodysplasia RAEB II had a major response of neutrophils and platelets. Two patients had minor responses with transient clearance of peripheral blasts or improvement of hematopoiesis, and two patients achieved disease stabilization for 3 and 14 months. WT1 transcripts as molecular disease marker decreased in 5 of these 6 patients and also in 4 of 5 high-risk patients. No significant toxicity occurred. The generation of a WT1-specific T cell response in peripheral blood and bone marrow was detected in 9 of 13 patients by tetramer analysis and 8 of 13 patients by intracellular cytokine staining. Conclusion: These results show that WT1 vaccination can induce functional T cell responses associated with antileukemic activity and warrant trials of WT1 vaccination in patients at high risk of relapse and with WT1-expressing carcinomas. No significant financial relationships to disclose.

WT1-Peptide Vaccination in Patients With Acute Myeloid Leukemia Shows High Immunogenicity Associated With Clinical Activity

WT1-Peptide Vaccination in Patients With Acute Myeloid Leukemia Shows High Immunogenicity Associated With Clinical Activity