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

Stasi, Antonio Di; Jiménez, Antonio; Minagawa, Kentaro; Al‐Obaidi, Mustafa; Rezvani, Katayoun

doi:10.3389/fimmu.2015.00036

Cited by 91 publications

(79 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…27 Several groups have vaccinated patients with WT1 peptides and reported both immunologic and clinical responses. [21][22][23]28 Generally, these studies have used HLA-restricted class I peptides (either HLA-A*02:01 or HLA-A*24:02) to elicit CD8 1 cytotoxic T lymphocyte (CTL) responses. Potential therapeutic activity has been demonstrated by both clinical response and decreases in measurable MRD (WT1) transcript levels.…”

Section: Discussionmentioning

confidence: 99%

Phase 2 trial of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia

et al. 2018

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Phase 2 trial of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia

et al. 2018

View full text Add to dashboard Cite

show abstract

“…20 Finally, a promising approach in reducing relapse rates could be vaccination concepts with peptides such as WT-1, which is highly expressed in the majority of AML. 21 It is of note that three patients died after aHCT because of a tertiary malignancy: in two patients, a solid cancer of the tongue and hypopharynx occurred, respectively, most likely not due to the pre-therapy but rather due to lifestyle, whereas one patient developed an EBV-associated post-transplant lymphoproliferative disorder.…”

Section: Discussionmentioning

confidence: 99%

Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation

Finke

Schmoor

Bertz

et al. 2016

Bone Marrow Transplant

View full text Add to dashboard Cite

The outcome of patients with therapy-related myelodysplasia (t-MDS) or t-AML is very poor. The only curative treatment option implements allogeneic hematopoietic cell transplantation (aHCT); however, long-term follow-up data beyond 5 years are scarce. Here we report on a cohort of 79 consecutive patients with a median age of 58 years (range (r): 20-76) at transplantation and a median follow-up of 7.5 years (r: 0.07-19.0). Only 19 (24.1%) patients were in CR before aHCT. Non-relapse mortality and relapse rates were 23% (95% confidence interval, 15-35%) and 42% (32-55%) at 5 years, and 32% (22-46%) and 44% (34-57%) at 10 years, respectively. Disease-free survival (DFS) and overall survival (OS) rates were 35% (24-46%) and 38% (27-49%) at 5 years, and 24% (14-36%) and 24% (13-36%) at 10 years, respectively. Although cytogenetic aberrations were associated with shorter DFS and higher relapse risk, persistent disease at the time of transplantation, an unrelated donor and patient age were not associated with shorter OS. In conclusion, long-term survival beyond 10 years of t-MDS/t-AML patients after aHCT is possible, even for refractory patients. Therefore, early donor search and rapid transplantation are warranted, also to decrease the risk of disease-related deterioration of patients' performance status.Bone Marrow Transplantation (2016) 51, 771-777; doi:10.1038/bmt.2015.338; published online 11 January 2016 INTRODUCTION Cytotoxic agents, especially alkylating and topoisomerase II targeting drugs, as well as ionizing radiotherapy in the successful treatment of most cancer types and to some extent also in nonmalignant diseases, bear a significant long-term risk of developing therapy-related malignancies such as myelodysplasia (t-MDS) and t-AML. 1,2 Despite intensive efforts to reduce the risk of developing t-MDS/t-AML by using fewer cycles of dose-intense chemotherapy for a given primary disease and thus to decrease cumulative doses, this late occurring side effect remains a challenging clinical problem. 3 Treatment of t-MDS/t-AML, which often occurs with other comorbidities, is complex and the outcome of patients treated with low-or even high-dose chemotherapy alone remains poor. Beyond other factors, this is especially attributed to older age, therapy resistance and cytogenetic abnormalities including monosomies or complex karyotypes. 4,5 In recent years, it has become evident that the most successful curative treatment concept for t-MDS/t-AML patients resulting in substantial remission rates implements allogeneic hematopoietic cell transplantation (aHCT). Using a myeloablative conditioning regimen in 77% of patients in a cohort of 868 patients with a median age of 40 years, Litzow et al. 6 reported an overall survival (OS) rate of 22% (95% confidence interval (CI), 19-26%) after 5 years, although the non-relapse mortality (NRM) and relapse rate at that time were 48% (95% CI, 44-51%) and 31% (95% CI, 28-34%), respectively. In another study from the European Group for Blood and Marrow Transplantation, Kröger et al. 7...

show abstract

“…Clinically meaningful responses have been reported in several trials in both AML and MDS patients, with associated increases in WT1-specific T-cell frequencies (Table 2). 68 Given the fact that WT1 is normally expressed in several tissues and plays a role in hematopoiesis, concern had been raised about the potential for WT1-vaccine therapies to elicit autoimmune reactions. However, this has not been reported thus far.…”

mentioning

confidence: 99%

Wilms tumor 1 mutations in the pathogenesis of acute myeloid leukemia

Rampal

Figueroa

2016

Haematologica

View full text Add to dashboard Cite

IntroductionThe observations that the Wilms tumor 1 (WT1) protein is expressed in the majority of cases of acute myeloid leukemia (AML), and in addition, is mutated in a proportion of AML cases has led to extensive work over the last several decades to determine the mechanistic role of WT1 in AML. The fact that WT1 may be either overexpressed or mutated has given rise to the concept that it may act as both a tumor suppressor and oncogene, depending on the context. To date, much of the mechanistic work on WT1 has centered on its function as a transcription factor and the role of its many isoforms. However, more recent work stemming from largescale genomic studies in AML has revealed a new role for WT1 in epigenetic regulation. Indeed, work by several groups has demonstrated that WT1 appears to play a role along with TET proteins in mediating 5-hydroxymethylation of cytosines. These novel observations have given rise to an enhanced understanding of the complexity of this protein and its pathogenic role in leukemogenesis. Herein, we seek to review the major concepts and findings with regard to WT1 in oncogenesis and normal hematopoiesis, as well as any therapeutic strategies that may arise from these observations. WT structure and functionThe WT1 gene was initially identified as an inherited predisposition allele in probands with familial Wilms tumor.1,2 Numerous WT1 missense and nonsense mutations have been described in inherited and sporadic Wilms tumors, a pediatric malignancy affecting the kidneys.3,4 WT1 mutations are identified in approximately 20% of Wilms tumors, and are seen in patients with a familial disposition to these tumors. Wilms tumor is also associated with the Denys-Drash syndrome (DDS), encompassing Wilms tumor, congenital nephrotic syndrome, and XY pseudohermaphroditism, which results from point mutations in WT1. 5,6 Mutations in the intron 9 splice site have been identified in patients with Frasier syndrome, a developmental condition that affects kidneys and genitalia. 7 In addition, WT1 has been implicated in a number of other malignancies, including desmoplastic small cell tumor, breast cancer, retinoblastoma, and lung carcinoma. 8,9 In lung cancer, Wt1 has been shown to play a role in murine lung cancer models driven by Kras mutations where deletion or suppression of Wt1 resulted in senescence of primary murine cells expressing Kras, but had no effect on wild type cells. 10 Furthermore, loss of Wt1 led to decreased proliferation and tumor burden in Kras-driven lung carcinoma, © Ferrata Storti Foundation thus implicating Wt1 as a necessary component of Krasdriven oncogenesis. Taken together, these observations indicate that a spectrum of mutations in WT1 can lead to both inherited developmental syndromes and cancer predisposition.The WT1 protein contains an N-terminal transactivation domain and a C-terminus with four zinc-fingers that share DNA binding motifs with EGR1 1 (Figure 1). Four major WT1 isoforms result from differences in alternative splicing. These isoforms arise through...

show abstract

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

Cited by 91 publications

References 51 publications

Phase 2 trial of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia

Phase 2 trial of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia

Long-term follow-up of therapy-related myelodysplasia and AML patients treated with allogeneic hematopoietic cell transplantation

Wilms tumor 1 mutations in the pathogenesis of acute myeloid leukemia

Contact Info

Product

Resources

About