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PEPTIDE VACCINATION AGAINST CANCER TESTIS ANTIGENS IN COMBINATION WITH AZACITIDINE FOR PATIENTS WITH MYELODYSPLASTIC SYNDROME AND ACUTE MYELOID LEUKEMIA: AN ONGOING PHASE I STUDY
Author(s): ,
Staffan Holmberg
Affiliations:
Dept. of Hematology,Herlev Hospital,Herlev,Denmark
,
Anne Ortved Gang
Affiliations:
Dept. of Hematology,Herlev Hospital,Herlev,Denmark
,
Inge Marie Svane
Affiliations:
Center for Cancer Immune Therapy,Herlev Hospital,Herlev,Denmark
,
Inge Høgh Dufva
Affiliations:
Dept. of Hematology,Herlev Hospital,Herlev,Denmark
Sine Reker Hadrup
Affiliations:
Section for Vaccinology and Immunology,Technical University of Denmark,Copenhagen,Denmark
(Abstract release date: 05/19/16) EHA Library. Holmberg S. 06/09/16; 134815; PB1915
Dr. Staffan Holmberg
Dr. Staffan Holmberg
Contributions
Abstract
Abstract: PB1915

Type: Publication Only

Background
Myelodysplastic Syndrome (MDS) is a clonal disorder and characterized by increasing bone marrow failure due to accumulation of genetic and epigenetic changes in hematopoietic stem cells. Patients with high-risk disease have a poor prognosis and a high risk of progression to Acute Myeloid Leukemia (AML). The dysplastic cells harbor chromosomal breakage, point mutations and promoter hyper-methylation of tumor suppressor genes.For most patients, who are not eligible for bone marrow transplantation, hypomethylating agents, such as azacitidine (AZA), are currently the only treatment option. The demand for more effective therapies in this patient group is huge. Though the mechanism of AZA is not fully elucidated re-expression of tumor suppressor genes can serve as a mechanism for growth arrest. In addition, there is accumulating evidence for an up-regulation of cancer testis antigens (CTA), which could lead to increased immune recognition of tumor cells and immune-mediated tumor cell killing. CTA’s are known to be immunogenic and are only expressed at immunoprivileged sites and on malignant cells, making them attractive as targets for therapeutic cancer vaccination. 

Aims
We have set up a phase I trial where we combine the treatment of hypomethylating agents with a peptide vaccine, to boost an immune response against four selected tumor associated antigens which are known to be regulated by methylation, in patients with high-risk MDS and AML. 

Methods
For this vaccine specifically three CTA’s were chosen where abundant re-expression has been shown following AZA treatment, including NY-ESO-1, MAGE-A3 and PRAME. WT-1 is additionally included as this protein has proven to be an important antigen in hematological malignancies and is likewise upregulated in response to AZA treatment. The peptides are between 25-29 mer and include a broad selection of HLA class I and II epitopes. Each vaccine contains ~50 µg of each peptide and is mixed as a suspension with Montanide ISA-51. The use of synthetic long peptides has shown superior effect in contrast to minimal peptide sequences. They contain several CD4 and CD8 T- cell epitopes for a broad range of HLA types, and thus allowing inclusion of participants without prior selection based on HLA expression.Inclusion commence after six courses of AZA and following a treatment evaluation. If there is continued indication of AZA treatment, a set of three vaccinations is given together with the following three courses of AZA. An additional vaccination is then given every six months for two years or until there is unfavorable disease progression. 

Results
At the time of writing we are planning for the inclusion of our first patient which is expected to take place in late March 2016. Preliminary results from the first vaccinations will be available to show at the conference. 

Conclusion
15 patients from the department of Hematology at Herlev Hospital, Copenhagen, Denmark, will be included starting March 2016. The primary endpoint is to elucidate whether the combination of AZA and peptide vaccination is a safe and tolerable treatment, but specific immune responses and clinical efficacy will also be evaluated. 

Session topic: E-poster

Keyword(s): Cancer vaccine, Clinical trial, Hypomethylation, MDS/AML
Abstract: PB1915

Type: Publication Only

Background
Myelodysplastic Syndrome (MDS) is a clonal disorder and characterized by increasing bone marrow failure due to accumulation of genetic and epigenetic changes in hematopoietic stem cells. Patients with high-risk disease have a poor prognosis and a high risk of progression to Acute Myeloid Leukemia (AML). The dysplastic cells harbor chromosomal breakage, point mutations and promoter hyper-methylation of tumor suppressor genes.For most patients, who are not eligible for bone marrow transplantation, hypomethylating agents, such as azacitidine (AZA), are currently the only treatment option. The demand for more effective therapies in this patient group is huge. Though the mechanism of AZA is not fully elucidated re-expression of tumor suppressor genes can serve as a mechanism for growth arrest. In addition, there is accumulating evidence for an up-regulation of cancer testis antigens (CTA), which could lead to increased immune recognition of tumor cells and immune-mediated tumor cell killing. CTA’s are known to be immunogenic and are only expressed at immunoprivileged sites and on malignant cells, making them attractive as targets for therapeutic cancer vaccination. 

Aims
We have set up a phase I trial where we combine the treatment of hypomethylating agents with a peptide vaccine, to boost an immune response against four selected tumor associated antigens which are known to be regulated by methylation, in patients with high-risk MDS and AML. 

Methods
For this vaccine specifically three CTA’s were chosen where abundant re-expression has been shown following AZA treatment, including NY-ESO-1, MAGE-A3 and PRAME. WT-1 is additionally included as this protein has proven to be an important antigen in hematological malignancies and is likewise upregulated in response to AZA treatment. The peptides are between 25-29 mer and include a broad selection of HLA class I and II epitopes. Each vaccine contains ~50 µg of each peptide and is mixed as a suspension with Montanide ISA-51. The use of synthetic long peptides has shown superior effect in contrast to minimal peptide sequences. They contain several CD4 and CD8 T- cell epitopes for a broad range of HLA types, and thus allowing inclusion of participants without prior selection based on HLA expression.Inclusion commence after six courses of AZA and following a treatment evaluation. If there is continued indication of AZA treatment, a set of three vaccinations is given together with the following three courses of AZA. An additional vaccination is then given every six months for two years or until there is unfavorable disease progression. 

Results
At the time of writing we are planning for the inclusion of our first patient which is expected to take place in late March 2016. Preliminary results from the first vaccinations will be available to show at the conference. 

Conclusion
15 patients from the department of Hematology at Herlev Hospital, Copenhagen, Denmark, will be included starting March 2016. The primary endpoint is to elucidate whether the combination of AZA and peptide vaccination is a safe and tolerable treatment, but specific immune responses and clinical efficacy will also be evaluated. 

Session topic: E-poster

Keyword(s): Cancer vaccine, Clinical trial, Hypomethylation, MDS/AML

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