scholarly journals Induction of Immune Response after Allogeneic Wilms' Tumor 1 Dendritic Cell Vaccination and Donor Lymphocyte Infusion in Patients with Hematologic Malignancies and Post-Transplantation Relapse

2016 ◽  
Vol 22 (12) ◽  
pp. 2149-2154 ◽  
Author(s):  
Nirali N. Shah ◽  
David M. Loeb ◽  
Hahn Khuu ◽  
David Stroncek ◽  
Tolu Ariyo ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cell ◽  
Wilms Tumor ◽  
Hematologic Malignancies ◽  
Donor Lymphocyte Infusion ◽  
Dendritic Cell Vaccination ◽  
Post Transplantation ◽  
Wilms Tumor 1

scholarly journals Enzyme-Linked Immunosorbent Spot Assay for the Detection of Wilms’ Tumor 1-Specific T Cells Induced by Dendritic Cell Vaccination

Biomedicines ◽  
2015 ◽  
Vol 3 (4) ◽  
pp. 304-315 ◽  
Author(s):  
Yumiko Higuchi ◽  
Terutsugu Koya ◽  
Miki Yuzawa ◽  
Naoko Yamaoka ◽  
Yumiko Mizuno ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cell ◽  
Wilms Tumor ◽  
Dendritic Cell Vaccination ◽  
Wilms Tumor 1

scholarly journals Induction of complete and molecular remissions in acute myeloid leukemia by Wilms' tumor 1 antigen-targeted dendritic cell vaccination

2010 ◽  
Vol 107 (31) ◽  
pp. 13824-13829 ◽  
Author(s):  
V. F. Van Tendeloo ◽  
A. Van de Velde ◽  
A. Van Driessche ◽  
N. Cools ◽  
S. Anguille ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dendritic Cell ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Dendritic Cell Vaccination ◽  
Wilms Tumor 1 ◽  
Acute Myeloid

scholarly journals Dendritic cell–based immunotherapy targeting Wilms’ tumor 1 in patients with recurrent malignant glioma

2015 ◽  
Vol 123 (4) ◽  
pp. 989-997 ◽  
Author(s):  
Keiichi Sakai ◽  
Shigetaka Shimodaira ◽  
Shinya Maejima ◽  
Nobuyuki Udagawa ◽  
Kenji Sano ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Malignant Glioma ◽  
Stable Disease ◽  
Wilms Tumor ◽  
Malignant Gliomas ◽  
Tumor Lysate ◽  
Dc Vaccine ◽  
Pulsed Dc ◽  
Wilms Tumor 1 ◽  
Vaccination Therapy

OBJECT Dendritic cell (DC)-based vaccination is considered a potentially effective therapy against advanced cancer. The authors conducted a Phase I study to investigate the safety and immunomonitoring of Wilms’ tumor 1 (WT1)-pulsed DC vaccination therapy for patients with relapsed malignant glioma. METHODS WT1-pulsed and/or autologous tumor lysate-pulsed DC vaccination therapy was performed in patients with relapsed malignant gliomas. Approximately 1 × 107 to 2 × 107 pulsed DCs loaded with WT1 peptide antigen and/or tumor lysate were intradermally injected into the axillary areas with OK-432, a streptococcal preparation, at 2-week intervals for at least 5–7 sessions (1 course) during an individual chemotherapy regimen. RESULTS Ten patients (3 men, 7 women; age range 24–64 years [median 39 years]) with the following tumors were enrolled: glioblastoma (6), anaplastic astrocytoma (2), anaplastic oligoastrocytoma (1), and anaplastic oligodendroglioma (1). Modified WT1 peptide–pulsed DC vaccine was administered to 7 patients, tumor lysate-pulsed DC vaccine to 2 patients, and both tumor lysate–pulsed and WT1-pulsed DC vaccine to 1 patient. The clinical response was stable disease in 5 patients with WT1-pulsed DC vaccination. In 2 of 5 patients with stable disease, neurological findings improved, and MR images showed tumor shrinkage. No serious adverse events occurred except Grade 1–2 erythema at the injection sites. WT1 tetramer analysis detected WT1-reactive cytotoxic T cells after vaccination in patients treated with WT1-pulsed therapy. Positivity for skin reaction at the injection sites was 80% (8 of 10 patients) after the first session, and positivity remained for these 8 patients after the final session. CONCLUSIONS This study of WT1-pulsed DC vaccination therapy demonstrated safety, immunogenicity, and feasibility in the management of relapsed malignant gliomas.

Wilms Tumor 1 Gene (WT1) Isoforms in Leukemia and Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4265-4265
Author(s):  
Aihong Li ◽  
Ulla-Britt Westman ◽  
Irina Golovleva ◽  
Jeffery L. Kutok ◽  
Lewis B. Silverman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Residual Disease ◽  
Wilms Tumor ◽  
Hematologic Malignancies ◽  
Expression Levels ◽  
Variable Expression ◽  
Myeloid Leukemias ◽  
Wilms Tumor 1 ◽  
Pediatric Aml

Abstract The Wilms tumor 1 gene (WT1) acts as a transcriptional activator or repressor and is important for normal development. Evidence has accumulated to show that WT1 is oncogenic in acute leukemia and in some solid tumors. WT1 has 4 major isoforms and each encoded polypeptide is thought to make a contribution to normal gene function, but no data are available on their expression in hematologic malignancies. We have analyzed the expression of WT1 and its four isoforms (A, B, C, and D) in 187 diagnostic samples from patients with leukemia or lymphoma. WT1 RNA expression was detected in 9/10 (90%) chronic myeloid leukemias (CML), in 41/47 (87%) of acute myeloid leukemias (AML), in 38/56 (68%) acute lymphoblastic leukemias (ALL) and in 22/74 (30%) of malignant lymphomas. The highest expression levels were found in pre-B ALL and in AML samples. Aggressive lymphomas were more often WT1 positive and with higher levels compared to indolent cases (p < 0.01). Only 9% of AML and ALL bone marrows in complete remission (n=22) showed detectable WT1 expression and all benign lymph nodes studied (n=11) were WT1 negative. The different WT1 isoforms demonstrated highly variable expression levels with isoform A as the most common form in all tumor types. There was no difference in isoform expression between T-ALL and B-lineage ALL. However, AML-M3 demonstrated a significantly higher expression of isoform A compared to other AML subtypes (p<0.01). T-cell lymphoma had a higher level of all isoforms than other lymphoma types (p<0.01). We observed a high concordance regarding WT1 expression levels between matched samples from peripheral blood and bone marrow in T-ALL (R=0.982, P<0.01). A significant reduction in WT1 levels was demonstrated during chemotherapy in two pediatric AML patients. In conclusion, WT1 expression was coupled to malignancy in both bone marrow and lymph node samples and thus could be considered as a potential molecular marker for minimal residual disease detection in acute leukemia. All four WT1 isoforms could be detected in most WT1 positive samples, but their functional significance remains to be clarified.

A Pilot Trial of WT1 Peptide-Loaded Allogeneic Dendritic Cell Vaccine and Donor Lymphocyte Infusion for WT1-Expressing Hematologic Malignancies and Post-Transplant Relapse

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3055-3055
Author(s):  
Nirali N Shah ◽  
David Loeb ◽  
Hahn Khuu ◽  
David Stroncek ◽  
Mark Raffeld ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Immune Responses ◽  
Peripheral Blood ◽  
Lymphoblastic Leukemia ◽  
Pilot Trial ◽  
Hematologic Malignancies ◽  
Donor Lymphocyte Infusion ◽  
Delayed Type Hypersensitivity ◽  
Hematopoietic Stem ◽  
Clinical Responses

Abstract Abstract 3055 Background: Treatment of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains challenging. The Wilms' tumor 1 (WT1) gene product is a tumor-associated antigen that is expressed in acute leukemia and other hematologic malignancies with limited expression in normal tissues. This pilot trial incorporates antigen-specific immunotherapy and allogeneic adoptive cell transfer for pediatric and adult patients with relapsed hematologic malignancies after alloHSCT. The primary objectives are to assess safety and feasibility of a peptide-loaded donor-derived dendritic cell (DC) vaccine and donor lymphocyte infusion (DLI) designed to enhance the graft-vs -leukemia effect. Secondary objectives are to determine if immunologic and clinical responses to WT1 specific peptides can be generated by this novel vaccine strategy after alloHSCT. Design: HLA-A2+ patients with WT1-expressing hematologic malignancies that have relapsed after alloHSCT are eligible. Donor-derived DC vaccines are given every 2 weeks for 6 doses and DLI every 4 weeks for 3 doses. Peripheral blood monocyte-derived DCs are loaded with a combination of three HLA-A2 binding WT1 peptides (WT1 37–45; WT1 126–134; WT1 187–195) linked to the 11-mer HIV TAT protein transduction domain peptide (47–57) designed to enhance antigen presentation. The DCs are generated from donor peripheral blood monocytes that are separated from DLI collected by apheresis. Monocytes are incubated with GM-CSF and IL-4 followed by maturation with LPS and IFN-g. WT1 expression is assessed using immunohistochemistry and/or quantative RT-PCR. Study endpoints included toxicity, feasibility, and antigen-specific immune and clinical responses. Results: 4 patients, aged 9–19 years have been treated to date, 3 with acute lymphoblastic leukemia (ALL) and one with Hodgkin lymphoma (HL). Donors were matched siblings in 3 cases and a 10/10 HLA matched father in one case. Vaccines were successfully produced from all donors. All patients tolerated vaccine and DLI administrations well. The most common adverse events were mild, reversible pain and pruritus at vaccine administration and delayed type hypersensitivity (DTH) skin test sites. One patient developed Grade I skin GVHD that did not require treatment. Immune responses were observed in all 3 patients with ALL. ELISPOT was considered positive when it was at least two times greater than and had at least 10 spots more than background. 3 of 4 (75%) patients had positive ELISPOT responses to WT1 peptides. 3 of 4 (75%) patients had positive DTH responses to the keyhole limpet hemocyanin (KLH) control and 2 of 4 (50%) to the WT1 peptides. Median overall survival was 12 months. 1 patient remains in remission 12 months after initiation of therapy and 3 have died of disease. All donors tolerated apheresis well and there were no complications from donor procedures. Conclusions: This novel allogeneic immunotherapy regimen is feasible, well-tolerated and can induce immune responses in the allogeneic setting. Accrual is ongoing. Disclosures: Off Label Use: This is a pilot clinical trial of an investigational cancer vaccine.

Clinical and Immunological Response Following hTERT/Survivin mRNA-Loaded Dendritic Cell Vaccination Combined With Ex-Vivo Expanded T Cell Transfer In Melanoma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4487-4487
Author(s):  
Gunnar Kvalheim ◽  
Iris Bigalke ◽  
Siri Torhaug ◽  
Marianne Lundby ◽  
Camilla Mollat ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Ex Vivo ◽  
Dendritic Cell Vaccination ◽  
Cell Injection ◽  
Blood Samples ◽  
Melanoma Patients ◽  
T Cell Transfer

New immunotherapy strategies have recently been developed combining peptide or dendritic cell (DC) vaccination with infusion of vaccine-primed and ex vivo expanded T cells. The hypothesis is that adoptive transfer of ex vivo expanded tumor specific T cells can improve progression-free and overall survival by restoring anti-tumor immunity. In a phase I/II clinical trial on malignant melanomas stage IV patients received DC vaccination prior to transfer of ex vivo expanded T cells. Our strategy was to target hTERT and survivin since both is highly expressed in most cancers. The vaccine consisted of autologous DCs loaded with hTERT and survivin mRNA. Prior to each DC vaccination the patients received 5 days of Temozolomide treatment to reduce the number of regulatory T cells (Treg). Following 2 monthly DC vaccinations, blood samples were tested for immune response against hTERT and survivin overlapping peptides. Immune responders were offered injection of T cells. The Elutra fraction of T cells was depleted of Treg using Dynabeads CD25 prior to expansion with Dynabeads CD3/CD28 in a WAVE bioreactor. After 10 days the beads were removed and T cells were washed. 3x1010 expanded T cells were injected fresh and DC vaccination was continued. Prior to T cell infusion, the patients received non-myeloablative conditioning with Fludarabine and Cyclophosphamide Here we present the results from three patients receiving expanded T cells. Immune response against hTERT and survivin peptides were detected in blood samples from 7 to 11 weeks of DC vaccination. After 4-7 months of DC vaccination the T cells were expanded for 10 days prior to injection. DC vaccination was continued 1 day after T cell injection. Infused T cells expanded significantly in vivo and in two of the three patients currently tested both patients showed response against hTERT and survivin peptides. Blood samples taken monthly after T cell injection demonstrated immune response against the same peptides. In one of patients the number of Treg was high (> 4%) before and during vaccination and returned to low numbers (<1%) after T cell injection. Since these findings might explain the beneficial effect of the vaccination we are currently investigating if the number of Tregs in blood show the same profile in the two other patients. Progression free survival (PFS) in the three patients was 31,20 and 11 months respectively. Patients with the shortest PFS relapsed very shortly after the T-cell infusion in spite of an objective immunresponse following the last DC vaccine. Metastatic melanoma patients included in this study given DC vaccines without T-cells had a median PFS of 7 months (3-13). We therefore conclude that dendritic cell vaccination combined with ex-vivo expanded T cell transfer can be an efficient immunotherapy strategy in melanoma patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Phase I pilot study of Wilms tumor gene 1 peptide‐pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer

2015 ◽  
Vol 106 (4) ◽  
pp. 397-406 ◽  
Author(s):  
Shuhei Mayanagi ◽  
Minoru Kitago ◽  
Toshiharu Sakurai ◽  
Tatsuo Matsuda ◽  
Tomonobu Fujita ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dendritic Cell ◽  
Pilot Study ◽  
Phase I ◽  
Wilms Tumor ◽  
Dendritic Cell Vaccination ◽  
Wilms Tumor Gene ◽  
Tumor Gene
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