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WT1 vaccination (9 doses of WT-1:126-134 peptide (in Montanide adjuvant) administered concomitantly with GM-CSF (Sargramostim)

WT1 Peptide Vaccine

John Barrett, MD

This study will determine the safety and effectiveness of an experimental vaccine in controlling the abnormal growth of cells in patients with myelodysplastic syndrome (MDS, also known as myelodysplasia), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML). It will test whether the vaccine can increase the number of immune cells responding to the cancer and thereby slow progression of the illness, improve blood counts, reduce the need for transfusions of blood and platelets, or even achieve a disease remission. The vaccine contains part of a protein that is produced in large amounts by cells of patients with these cancers and an added substance called Montanide that helps the immune system respond to the vaccine. Sargramostim, another substances that boosts the immune response, is also given.

Patients 18 to 85 years of age with MDS, AML, ALL or CML may be eligible for this study. Candidates are screened with a medical history, physical examination, blood tests, chest x-ray and bone marrow biopsy. Women of childbearing age also have a pregnancy test.

Participants undergo the following:

* Chemotherapy entering the study.
* Leukapheresis to collect large amounts of white blood cells for infusion before vaccine administration.
* Participants may need placement of a central line (plastic tube, or catheter) in the upper part of the chest to be used for giving chemotherapy, blood or platelet transfusions, antibiotics and white blood cells, and for collecting blood samples.
* Weekly vaccine injections for nine weeks, given in the upper arm, upper leg or abdomen.
* Sargramostim injections following each vaccination.
* Standard of care treatment for MDS, AML, ALL or CML, which may include blood or platelet transfusions, growth factors, and drugs to control underlying disease and potential side effects of the vaccine.
* Weekly safety monitoring, including vital signs check, brief health assessment, blood tests and observation after the vaccination, on the day of each vaccination.
* Follow-up evaluations with blood tests and chest x-ray 3 weeks after the last vaccine dose and with blood tests and bone marrow biopsy 7 weeks after the last vaccine dose.

Leukemias and the related disorders myelodysplastic syndrome and myeloproliferative diseases represent a wide group of bone marrow stem cell malignancies. Some patients can be cured with chemotherapy or by allogeneic stem cell transplantation. However, standard treatment approaches are not effective for patients who become refractory to chemotherapy, those who relapse after transplantation and those with progressive disease. The management of such patients remains unsatisfactory and requires new treatment approaches other than chemotherapy.

The immunological graft-versus-leukemia (GVL) effect seen after allogeneic stem cell transplantation suggests that stimulating the patient's own T cell responses to hematological malignancies might also retard disease progression and even achieve disease remissions. Wilm's Tumor 1 (WT1) was identified as a target vaccine antigen because this antigen is over-expressed by cluster of differentiation 34 (CD34) plus stem cells of most patients with myeloid and lymphoid malignancies but not by normal marrow cells. A human leukocyte antigen (HLA-A0201) restricted peptide derived from the Wilm's Tumor (WT) protein is anticipated to induce T cell response against MDS and leukemic cells while sparing normal cells. Of note, about 40% of the population is HLA-A0201 positive.

Therefore we propose this Phase II trial, the second in a series of planned peptide vaccine research, which will evaluate the safety associated with an immunotherapy approach of lymphodepletion, lymphocyte infusion, and WT1 vaccination in select patients diagnosed with MDS, AML, ALL and CML. The WT1 vaccination will comprise of 9 doses of WT-1 peptide vaccines (in Montanide adjuvant) administered concomitantly with granulocyte macrophage- colony stimulating factor (GM-CSF) (Sargramostim).

The primary objectives will be to evaluate the efficacy and toxicity associated with the immunotherapy approach of lymphodepletion, lymphocyte infusion, and WT1 vaccination in selected patients with hematological malignancies.

Secondary objectives will include evaluation of disease response by following the numbers of WT1 expressing cells in blood, hematological measurements (reduction in marrow blast cells, changes in blood counts), transfusion dependence, and time to disease progression and survival.

The primary endpoint will be the side effects of treatment (toxicity and number of circulating WT1 specific T cells (efficacy ) measured through week 16 of the study (7 weeks after the last dose of vaccine).

Wilm's Tumor 1 (WT1) Peptide Vaccine for High Risk Hematologic Malignancy

Wilm's Tumor 1 (WT1) Peptide Vaccination for Patients With High Risk Hematological Malignancies

Minimum criterion for a cellular immune response was defined as the emergence of detectable T cell frequency against Willm's tumor 1 (WT1) when the pre-study analysis found no response, or a twofold increase in T cell frequency at any post vaccination time point

Clinical response of underlying malignancy to the vaccination

National Heart, Lung, and Blood Institute (NHLBI)

Principal Investigator

All 4 patients who were accrued went on to receive the vaccine

Subjects with hematologic malignancies will receive WT1 peptide vaccine to evaluate if the intervention will stimulate a protective immune response.

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Although there was one partial response at 7 weeks, this patient went on to relapse as well.

Consequently, all 4 patients had rapid relapses despite vaccination. Accrual was stopped at 4.

Minoo Battiwalla, MD

Cellular Immune Response

Complete response

Partial response

No response

All 4 patients who were accrued went on to receive the vaccine.

Complete Response (CR): defined as an absolute neutrophil count of ≥500/µL, platelet count of ≥75,000/µL, no leukemic blasts in the blood nor evidence of extramedullary leukemia, bone marrow (BM) with a cellularity of more than 20%, maturation of all three cell lineages, no Auer rods, and less than 5% bone marrow blast cells.

Partial response (PR): 50% reduction in marrow blasts, with an absolute neutrophil count (ANC) greater than 500/µL, and platelet count greater than 75000/µL.

No response: subjects who did not meet the above response criteria were defined as non-responders.

Disease Response

Overall Study

Lymphoma

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

This is a Phase II study evaluating the safety and efficacy of the WT1 peptide vaccine in patients who are in CR from Acute Myeloid Leukemia (AML).

Six vaccinations of the WT1 peptide preparation (1.0 ml of emulsion) will be administered on weeks 0, 2, 4, 6, 8, and 10. All vaccinations will be administered subcutaneously with vaccination sites rotated among extremities. Patients who are clinically stable and have not had disease progression, may receive up to 6 more vaccinations administered appropriately every month.

WT1 peptide vaccine

Peter Maslak, MD

To determine whether the WT1 vaccine causes an immune response which is safe and able to keep the leukemia from coming back.

The purpose of this study is to determine whether the WT1 vaccine causes an immune response which is safe and able to keep the leukemia from coming back. While vaccines have been used in infectious diseases like smallpox and measles,the idea about using vaccines in a cancer like AML/ALL is really a new use of the idea of vaccines.The WT-1 vaccine is made up of protein pieces that the immune system can recognize as abnormal. The doctor thinks that the WT-1 protein is important in AML/ALL and using some lab tests they are still able to find some of it in the bone marrow. By attacking this small amount of the protein they hope to get rid of any small amount of AML that is still in the body.

WT-1 Analog Peptide Vaccine in Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL)

Phase II Trial of a WT-1 Analog Peptide Vaccine in Patients in Complete Remission (CR) From Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL)

of the WT1 peptide vaccine administered to patients in CR from AML. Early toxicity will be assessed at weeks 2 and 4,. Routine toxicity assessments will continue throughout the trial. Any toxicity noted in the trial will be graded in accordance with Common Toxicity Criteria, version 4.0 (CTCAE 4.0) developed by the National Cancer Institute.

The primary efficacy measure is defined as overall survival at 3 years.

via CD4+ T cell proliferation, CD3+ T cell interferon- γ release (ELISPOT and / or flow cytometry) and WT1 peptide tetramer staining.

as measured by RT-PCR for WT1 transcript.

Sellas Life Sciences Group

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Wilm's Tumor 1 (WT1) Peptide Vaccine for High Risk Hematologic Malignancy	NCT00433745	Myelodysplastic... Acute Myeloid L... Chronic Myeloid...	WT1 Peptide Vac...	18 Years - 85 Years	National Institutes of Health Clinical Center (CC)
WT-1 Analog Peptide Vaccine in Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL)	NCT01266083	Acute Myeloid L... Acute Lymphobla...	WT1 peptide vac...	18 Years -	Sellas Life Sciences Group

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