scholarly journals Vaccination with synthetic analog peptides derived from WT1 oncoprotein induces T-cell responses in patients with complete remission from acute myeloid leukemia

Blood ◽  
2010 ◽  
Vol 116 (2) ◽  
pp. 171-179 ◽  
Author(s):  
Peter G. Maslak ◽  
Tao Dao ◽  
Lee M. Krug ◽  
Suzanne Chanel ◽  
Tatyana Korontsvit ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Peptide Vaccine ◽  
T Cell Responses ◽  
Interferon Γ ◽  
Delayed Type Hypersensitivity ◽  
Cell Responses ◽  
Acute Myeloid

Abstract A pilot study was undertaken to assess the safety, activity, and immunogenicity of a polyvalent Wilms tumor gene 1 (WT1) peptide vaccine in patients with acute myeloid leukemia in complete remission but with molecular evidence of WT1 transcript. Patients received 6 vaccinations with 4 WT1 peptides (200 μg each) plus immune adjuvants over 12 weeks. Immune responses were evaluated by delayed-type hypersensitivity, CD4+ T-cell proliferation, CD3+ T-cell interferon-γ release, and WT1 peptide tetramer staining. Of the 9 evaluable patients, 7 completed 6 vaccinations and WT1-specific T-cell responses were noted in 7 of 8 patients. Three patients who were HLA-A0201-positive showed significant increase in interferon-γ–secreting cells and frequency of WT1 tetramer-positive CD8+ T cells. Three patients developed a delayed hypersensitivity reaction after vaccination. Definite related toxicities were minimal. With a mean follow-up of 30 plus or minus 8 months after diagnosis, median disease-free survival has not been reached. These preliminary data suggest that this polyvalent WT1 peptide vaccine can be administered safely to patients with a resulting immune response. Further studies are needed to establish the role of vaccination as viable postremission therapy for acute myeloid leukemia. This study was registered at www.clinicaltrials.gov as #NCT00398138.

Stimulation of autologous proliferative and cytotoxic T-cell responses by “leukemic dendritic cells” derived from blast cells in acute myeloid leukemia

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2764-2771 ◽  
Author(s):  
Beth D. Harrison ◽  
Julie A. Adams ◽  
Mark Briggs ◽  
Michelle L. Brereton ◽  
John A. Liu Yin
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Dendritic Cells ◽  
T Cell ◽  
Myeloid Leukemia ◽  
T Cell Responses ◽  
Cell Responses ◽  
Antigen Presenting ◽  
Acute Myeloid ◽  
Stimulation Of

Abstract Effective presentation of tumor antigens is fundamental to strategies aimed at enrolling the immune system in eradication of residual disease after conventional treatments. Myeloid malignancies provide a unique opportunity to derive dendritic cells (DCs), functioning antigen-presenting cells, from the malignant cells themselves. These may then co-express leukemic antigens together with appropriate secondary signals and be used to generate a specific, antileukemic immune response. In this study, blasts from 40 patients with acute myeloid leukemia (AML) were cultured with combinations of granulocyte-macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor α, and development to DCs was assessed. After culture, cells from 24 samples exhibited morphological and immunophenotypic features of DCs, including expression of major histocompatibility complex class II, CD1a, CD83, and CD86, and were potent stimulators in an allogeneic mixed lymphocyte reaction (MLR). Stimulation of autologous T-cell responses was assessed by the proliferative response of autologous T cells to the leukemic DCs and by demonstration of the induction of specific, autologous, antileukemic cytotoxicity. Of 17 samples, 11 were effective stimulators in the autologous MLR, and low, but consistent, autologous, antileukemic cytotoxicity was induced in 8 of 11 cases (mean, 27%; range, 17%-37%). This study indicates that cells with enhanced antigen-presenting ability can be generated from AML blasts, that these cells can effectively prime autologous cytotoxic T cells in vitro, and that they may be used as potential vaccines in the immunotherapy of AML.

Expression of Tumor-Associated Antigens (TAAs) in Acute Myeloid Leukemia (AML) Correlated with Specific T Cell Responses and Survival.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 414-414
Author(s):  
Jochen Greiner ◽  
Michael Schmitt ◽  
Li Li ◽  
Krzysztof Giannopoulos ◽  
Katrin Bosch ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Clinical Outcome ◽  
Immune Responses ◽  
Dna Microarray ◽  
Myeloid Leukemia ◽  
T Cell Responses ◽  
Cell Responses ◽  
Acute Myeloid

Abstract Several Tumor-associated antigens (TAAs) are expressed in acute myeloid leukemia (AML) and elicit specific immune responses of CD8 positive T cells. These specific T cell responses against leukemic blasts expressing TAAs might play a critical role in the control of minimal residual disease (MRD) in AML. Therefore, we investigated whether TAAs inducing specific immune responses in AML patients were associated with the clinical outcome. A DNA-microarray analysis of 116 AML samples was performed to correlate expression of TAAs to the clinical outcome. In these AML patients specific T cell responses to TAAs were assessed by ELISPOT analysis, tetramer staining and chromium release assays. Quantitative RT-PCR based validation of our results demonstrated the power of DNA microarray technology. We found a significant correlation of high mRNA expression of the TAA G250/CA9 with a longer overall survival (P=0.022), a trend for better outcome in patients with high expression levels of PRAME (P=0.103), and a hint for RHAMM/HMMR. In contrast, for other TAAs like WT1, TERT, PRTN3, BCL2, and LAMR1 we found no correlation with clinical outcome of AML patients. Moreover, co-expression of RHAMM/HMMR, PRAME and G250/CA9 provided a favorable prognostic effect (P=0.005). We found specific T cell responses at high frequency for these three antigens in AML patients. Positive immune reactions were detected in 8/17 (47%) AML patients for RHAMM/HMMR-R3-derived, in 7/10 (70%) for PRAME-P3-derived, and in 6/10 (60%) for newly characterized G250/CA9-G2-derived peptides. We detected a significant increased immune response of AML patients in complete remission compared to AML patients with refractory disease (P<0.001). Furthermore, we could demonstrate specific lysis of T2 cells and AML blasts presenting these epitope peptides RHAMM/HMMR-R3, PRAME-P3 and G250/CA9-G2. In conclusion, the expression of the TAAs RHAMM/HMMR, PRAME and G250/CA9 can induce strong anti-leukemic immune responses of CD8 positive T cells possibly enabling the control of MRD in AML patients. Thus, the antigens RHAMM/HMMR, PRAME and G250/CA9 represent interesting target structures for polyvalent immunotherapeutic approaches in AML.

scholarly journals Mutated regions of nucleophosmin 1 elicit both CD4+ and CD8+ T-cell responses in patients with acute myeloid leukemia

Blood ◽  
2012 ◽  
Vol 120 (6) ◽  
pp. 1282-1289 ◽  
Author(s):  
Jochen Greiner ◽  
Yoko Ono ◽  
Susanne Hofmann ◽  
Anita Schmitt ◽  
Elmar Mehring ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Myeloid Leukemia ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Acute Myeloid

Abstract Mutations in the nucleophosmin gene (NPM1mut) are one of the most frequent molecular alterations in acute myeloid leukemia (AML), and immune responses may contribute to the favorable prognosis of AML patients with NPM1mut. In the present study, we were able to demonstrate both CD4+ and CD8+ T-cell responses against NPM1mut. Ten peptides derived from wild-type NPM1 and NPM1mut were subjected to ELISPOT analysis in 33 healthy volunteers and 27 AML patients. Tetramer assays against the most interesting epitopes were performed and Cr51-release assays were used to show the cytotoxicity of peptide-specific T cells. Moreover, HLA-DR–binding epitopes were used to test the role of CD4+ T cells in NPM1 immunogenicity. Two epitopes (epitopes #1 and #3) derived from NPM1mut induced CD8+ T-cell responses. A total of 33% of the NPM1mut AML patients showed immune responses against epitope #1 and 44% against epitope #3. Specific lysis of leukemic blasts was detected. To obtain robust immune responses against tumor cells, the activation of CD4+ T cells is crucial. Therefore, overlapping (OL) peptides were analyzed in ELISPOT assays and OL8 was able to activate both CD8+ and CD4+ T cells. The results of the present study show that NPM1mut induces specific T-cell responses of CD4+ and CD8+ T cells and therefore is a promising target for specific immunotherapies in AML.

scholarly journals PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model

Blood ◽  
2009 ◽  
Vol 114 (8) ◽  
pp. 1545-1552 ◽  
Author(s):  
Long Zhang ◽  
Thomas F. Gajewski ◽  
Justin Kline
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Cell Function ◽  
Immune Escape ◽  
Hematologic Malignancy ◽  
T Cell Responses ◽  
Cell Responses ◽  
Programmed Death ◽  
Acute Myeloid

Abstract Negative regulatory mechanisms within the solid tumor microenvironment inhibit antitumor T-cell function, leading to evasion from immune attack. One inhibitory mechanism is up-regulation of programmed death-ligand 1 (PD-L1) expressed on tumor or stromal cells which binds to programmed death-1 (PD-1) on activated T cells. PD-1/PD-L1 engagement results in diminished antitumor T-cell responses and correlates with poor outcome in murine and human solid cancers. In contrast to available data in solid tumors, little is known regarding involvement of the PD-1/PD-L1 pathway in immune escape by hematopoietic cancers, such as acute myeloid leukemia (AML). To investigate this hypothesis, we used the murine leukemia, C1498. When transferred intravenously, C1498 cells grew progressively and apparently evaded immune destruction. Low levels of PD-L1 expression were found on C1498 cells grown in vitro. However, PD-L1 expression was up-regulated on C1498 cells when grown in vivo. PD-1−/− mice challenged with C1498 cells generated augmented antitumor T-cell responses, showed decreased AML burden in the blood and other organs, and survived significantly longer than did wild-type mice. Similar results were obtained with a PD-L1 blocking antibody. These data suggest the importance of the PD-1/PD-L1 pathway in immune evasion by a hematologic malignancy, providing a rationale for clinical trials targeting this pathway in leukemia patients.

scholarly journals A blood dendritic cell vaccine for acute myeloid leukemia expands anti-tumor T cell responses at remission

2018 ◽  
Vol 7 (4) ◽  
pp. e1419114 ◽  
Author(s):  
Jennifer L. Hsu ◽  
Christian E. Bryant ◽  
Michael S. Papadimitrious ◽  
Benjamin Kong ◽  
Robin E. Gasiorowski ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Dendritic Cell ◽  
Myeloid Leukemia ◽  
T Cell Responses ◽  
Dendritic Cell Vaccine ◽  
Cell Vaccine ◽  
Cell Responses ◽  
Blood Dendritic Cell ◽  
Acute Myeloid

scholarly journals Helper T-Cell Responses and Clinical Activity of a Melanoma Vaccine With Multiple Peptides From MAGE and Melanocytic Differentiation Antigens

2008 ◽  
Vol 26 (30) ◽  
pp. 4973-4980 ◽  
Author(s):  
Craig L. Slingluff ◽  
Gina R. Petroni ◽  
Walter Olson ◽  
Andrea Czarkowski ◽  
William W. Grosh ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Peptide Vaccine ◽  
T Cell Responses ◽  
Delayed Type Hypersensitivity ◽  
Clinical Activity ◽  
Melanoma Vaccine ◽  
Cell Responses ◽  
Measurable Disease ◽  
Dose Levels

PurposeA phase I/II trial was performed to evaluate the safety and immunogenicity of a novel melanoma vaccine comprising six melanoma-associated peptides defined as antigenic targets for melanoma-reactive helper T cells. Source proteins for these peptides include MAGE proteins, MART-1/MelanA, gp100, and tyrosinase.Patients and MethodsThirty-nine patients with stage IIIB to IV melanoma were vaccinated with this six-peptide mixture weekly at three dose levels, with a preceding phase I dose escalation and subsequent random assignment among the dose levels. Helper T-lymphocyte responses were assessed by in vitro proliferation assay and delayed-type hypersensitivity skin testing. Patients with measurable disease were evaluated for objective clinical response by Response Evaluation Criteria in Solid Tumors.ResultsVaccination with the helper peptide vaccine was well tolerated. Proliferation assays revealed induction of T-cell responses to the melanoma helper peptides in 81% of patients. Among 17 patients with measurable disease, objective clinical responses were observed in two patients (12%), with response durations of 1 and 3.9+ years. Durable stable disease was observed in two additional patients for periods of 1.8 and 4.6+ years.ConclusionResults of this study support the safety and immunogenicity of a vaccine comprised of six melanoma helper peptides. There is also early evidence of clinical activity.

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

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2511-2511 ◽  
Author(s):  
U. Keilholz ◽  
A. Letsch ◽  
A. Asemissen ◽  
W. Hofmann ◽  
L. Uharek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Intracellular Cytokine Staining ◽  
T Cell Response ◽  
Antileukemic Activity ◽  
Acute Myeloid

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.

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