Immune responses to <scp>WT1</scp> in patients with <scp>AML</scp> or <scp>MDS</scp> after chemotherapy and allogeneic stem cell transplantation

Casalegno-Garduño, Rosaely; Schmitt, Anita; Spitschak, Alf; Greiner, Jochen; Wang, Lei; Hilgendorf, Inken; Hirt, Carsten; Ho, Anthony D.; Freund, Mathias; Schmitt, Michael

doi:10.1002/ijc.29909

Cited by 27 publications

(21 citation statements)

References 47 publications

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“…Increased OS in AML was recently found to correlate with reduced WT1 mRNA levels and WT1-specific CD8 1 T-cell responses in a cohort of patients with AML after chemotherapy and allo-HSCT. 34 The comparatively longer OS observed in patients with AML vaccinated with WT1/DCs is consistent with a meta-analysis indicating that DC vaccine therapy can offer OS benefit in patients with solid malignancies, including melanoma, prostate cancer, glioblastoma multiforme, and renal cell cancer.…”

Section: Discussionsupporting

confidence: 83%

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia

Anguille

Velde

Smits

et al. 2017

Blood

175

146

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Key Points• WT1 mRNA-electroporated DCs can prevent or delay relapse in 43% of patients with AML in remission after chemotherapy.• OS compares favorably with the new survival data from the Swedish Acute Leukemia Registry and correlates with molecular and WT1-specific CD8 1 T-cell responses.Relapse is a major problem in acute myeloid leukemia (AML) and adversely affects survival. In this phase 2 study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms' tumor 1 (WT1) messenger RNA (mRNA) as postremission treatment in 30 patients with AML at very high risk of relapse. There was a demonstrable antileukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of WT1 transcript levels, 5 of which were sustained after a median follow-up of 109.4 months. Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was higher in responders than in nonresponders (53.8% vs 25.0%; P 5 .01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25%, and 5-year relapse-free survival was higher in responders than in nonresponders (50% vs 7.7%; P < .0001). In patients age £65 and >65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared with 51.7% and 18% in the Swedish Acute Leukemia Registry. Long-term clinical response was correlated with increased circulating frequencies of polyepitope WT1-specific CD8 1 T cells. Long-term OS was correlated with interferon-g 1 and tumor necrosis factor-a 1 WT1-specific responses in delayed-type hypersensitivity-infiltrating CD8 1 T lymphocytes. In conclusion, vaccination of patients with AML with WT1 mRNA-electroporated DCs can be an effective strategy to prevent or delay relapse after standard chemotherapy, translating into improved OS rates, which are correlated with the induction of WT1-specific CD8 1 T-cell response. This trial was registered at www.clinicaltrials.gov as #NCT00965224. (Blood. 2017;130(15):1713-1721

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Section: Discussionsupporting

confidence: 83%

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia

Anguille

Velde

Smits

et al. 2017

Blood

175

146

View full text Add to dashboard Cite

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“…Moreover, WT1 expression can be used to detect minimal residual disease after HSCT [20]. However, although a recent meta-analysis was consistent with these previous reports, concluding that a higher WT1 expression had a slight poor prognostic impact on OS and disease-free survival [23], some studies did not find a relationship between WT1 expression at diagnosis and OS or event-free survival in AML patients [21,22].…”

Section: Discussionmentioning

confidence: 58%

Wilms Tumor 1 (WT1) mRNA Expression Level at Diagnosis Is a Significant Prognostic Marker in Elderly Patients with Myelodysplastic Syndrome

et al. 2016

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Background/Aims: A high expression of Wilms tumor 1 (WT1) mRNA occurs in most cases of acute leukemia and myelodysplastic syndrome (MDS). Although there are many reports suggesting that acute myeloid leukemia patients with high expression levels of WT1 mRNA have a relatively poor long-term survival, there are few reports addressing the relationship between WT1 levels and prognosis in MDS. Methods: We retrospectively analyzed 42 elderly patients with MDS whose WT1 levels at diagnosis were available, and we assessed the relationships between WT1 levels in peripheral blood and preexisting prognostic factors such as World Health Organization prognostic scores and Revised International Prognostic Scoring System risk categories, bone marrow blast percentages, and chromosomal abnormalities linked to a poor prognosis. We also evaluated the relationship between WT1 levels and prognosis. Results:WT1 levels were significantly different between high- and low-risk MDS patients (p < 0.05). There was a trend towards a significant difference between those with and those without poor prognostic chromosomal rearrangements (p = 0.051). Moreover, the overall survival and progression-free survival were significantly worse in elderly patients with higher levels of WT1 (p = 0.00039 and p = 0.00077, respectively). Conclusions: The WT1 mRNA expression level at diagnosis may be a significant independent prognostic marker for elderly patients with MDS.

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“…Tregs are known to induce a suppressive state in tumor-infiltrating CTLs, which favors leukemia development and growth ( 40 – 42 ). Clinically, in AML, the persistence of increased Tregs after chemotherapy is correlated with poor clinical outcome ( 43 ), which is paralleled with the exhaustion of leukemia-specific CTLs over time in association with disease relapse ( 44 , 45 ).…”

Section: Discussionmentioning

confidence: 99%

ATP Release from Chemotherapy-Treated Dying Leukemia Cells Elicits an Immune Suppressive Effect by Increasing Regulatory T Cells and Tolerogenic Dendritic Cells

et al. 2017

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Chemotherapy-induced immunogenic cell death can favor dendritic cell (DC) cross-priming of tumor-associated antigens for T cell activation thanks to the release of damage-associated molecular patterns, including ATP. Here, we tested the hypothesis that in acute myeloid leukemia (AML), ATP release, along with its well-known immune stimulatory effect, may also contribute to the generation of an immune suppressive microenvironment. In a cohort of AML patients, undergoing combined daunorubicin and cytarabine chemotherapy, a population of T regulatory cells (Tregs) with suppressive phenotype, expressing the immune checkpoint programmed cell death protein 1 (PD-1), was significantly increased. Moving from these results, initial in vitro data showed that daunorubicin was more effective than cytarabine in modulating DC function toward Tregs induction and such difference was correlated with the higher capacity of daunorubicin to induce ATP release from treated AML cells. DCs cultured with daunorubicin-treated AML cells upregulated indoleamine 2,3-dioxygenase 1 (IDO1), which induced anti-leukemia Tregs. These data were confirmed in vivo as daunorubicin-treated mice show an increase in extracellular ATP levels with increased number of Tregs, expressing PD-1 and IDO1+CD39+ DCs. Notably, daunorubicin failed to induce Tregs and tolerogenic DCs in mice lacking the ATP receptor P2X7. Our data indicate that ATP release from chemotherapy-treated dying cells contributes to create an immune suppressive microenvironment in AML.

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Immune responses to WT1 in patients with AML or MDS after chemotherapy and allogeneic stem cell transplantation

Cited by 27 publications

References 47 publications

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia

<b><i>Wilms Tumor 1 </i></b><b>(</b><b><i>WT1</i></b><b>)</b> mRNA Expression Level at Diagnosis Is a Significant Prognostic Marker in Elderly Patients with Myelodysplastic Syndrome

ATP Release from Chemotherapy-Treated Dying Leukemia Cells Elicits an Immune Suppressive Effect by Increasing Regulatory T Cells and Tolerogenic Dendritic Cells

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