Wilm's Tumor 1 Protein Vaccine to Treat Cancers of the Blood
|ClinicalTrials.gov Identifier: NCT00923910|
Recruitment Status : Completed
First Posted : June 18, 2009
Results First Posted : May 8, 2014
Last Update Posted : April 12, 2017
- Most patients with acute lymphoblastic leukemia (ALL) and many patients with acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML) and non-Hodgkin's lymphoma (NHL) have a protein called Wilm's Tumor 1 (WT1) in their cancer cells. This protein is thought to be able to influence the growth of these cancers.
- A vaccine made with the WT1 protein may boost the immune system to help fight these cancers in patients whose cancer cells contain the protein.
- To determine the safety, effectiveness and side effects of giving the WT1 vaccine and donor white blood cells to patients with AML, ALL, CML or NHL who have previously received standard treatment and undergone stem cell transplantation.
- To determine the immune response to the WT1 vaccine and donor white blood cells in these patients and to determine if the response is related to the amount of WT1 protein in the patient's cancer cells.
- Patients between 1 and 75 years of age with the blood antigen human leukocyte antigen (HLA-A2) and the WT1 cancer protein who have persistent or recurrent blood cancers after stem cell transplantation.
- The prior stem cell transplant donor must be willing to provide additional cells, which will be used to prepare the cellular vaccines and for donor lymphocyte (white blood cell) infusions.
- Patients are given the WT1 vaccine every 2 weeks for 6 weeks (weeks 0, 2, 4, 6, 8, 10). Each vaccination consists of two injections in the upper arm or thigh.
- On weeks 0, 4 and 8, patients also receive white blood cells from a donor to enhance the immune response. The cells are also given as a 15- to 30-minute infusion through a vein about 1 hour after the vaccine injection. Donor infusions are given only to patients with mild or no graft-vs-host disease resulting from their prior stem cell transplantation.
- Periodic physical examinations, blood and urine tests, scans to evaluate disease and other tests as needed are done for 12 months after enrollment in the study.
|Condition or disease||Intervention/treatment||Phase|
|Leukemia, Acute Myelogenous (AML) Leukemia, Acute Lymphocytic (ALL) Leukemia, Chronic Myelogenous (CML) Myelodysplastic Syndrome (MDS) Non-Hodgkin's Lymphoma (NHL)||Drug: WT1 Peptide-Pulsed Dendritic Cells Drug: Donor Lymphocytes Drug: IL-4 Drug: KLH Drug: WT1 Peptides Drug: Endotoxin Drug: Diphenhydramine Drug: Acetaminophen||Phase 1 Phase 2|
- Efforts to incorporate anti-tumor immunotherapy at stages of minimal residual disease (MRD) burden are limited by profound host immune depletion associated with standard anti-cancer therapies.
- Allogeneic blood and marrow stem cell transplantation (SCT) can be curative for a number of hematologic malignancies. Part of the success of this approach is an allogeneic immunologic reaction that has been demonstrated to play a role in the eradication of residual malignant disease after transplant in certain cancers (the so called graft-versus-leukemia, GVL, or graft-versus-tumor, GVT, effect). Nonetheless, relapse remains the primary cause of treatment failure after allogeneic SCT.
- The Wilm's tumor 1 (WT1) gene product is a tumor-associated antigen that represents a potential target for immunotherapy in a wide array of cancers. WT1 is expressed in most cases of acute leukemia and in many cases of chronic myelogenous leukemia and myelodysplastic syndromes. Importantly, WT1 has limited expression in normal tissues beyond embryogenesis. This trial represents an attempt to incorporate antigen-specific immunotherapy in the setting of allogeneic adoptive cell transfer.
- To determine the safety, toxicity, and feasibility of donor-derived dendritic cell vaccination and donor lymphocyte infusion (DLI) after allogeneic SCT.
- To determine the frequency and severity of graft-vs.-host disease (GVHD) in patients treated with peptide-loaded donor-derived dendritic cell vaccination and donor lymphocyte infusion (DLI).
- To evaluate whether immunologic responses to WT1-specific peptides can be generated by peptide-loaded donor-derived dendritic cell vaccination and DLI after allogeneic SCT.
- To evaluate whether clinical responses to WT1-specific peptides can be generated by peptide-loaded donor-derived dendritic cell vaccination and DLI after allogeneic SCT.
- To evaluate whether immunologic and/or clinical responses may be associated with the degree of WT1 expression by malignant cells or pre-existing donor anti-WT1 immunity.
- HLA-A2 plus patients may be enrolled on this trial if they have relapsed or residual disease following allogeneic SCT for a WT1 expressing hematologic malignancy.
- Donors from the previous SCT, related or unrelated, must be 5- or 6- antigen genotypic HLA-matched (single HLA-A or B locus mismatch allowed) and HLAA2 plus.
- This is a pilot study, the primary aim of which is to assess safety and feasibility of this novel vaccine strategy aimed to enhance the GVL effect after allogeneic SCT.
- Donor-derived dendritic cells prepared from peripheral blood monocytes will be loaded with a combination of three WT1-derived peptides. These peptides are each comprised of one WT1-derived oligomeric epitope known to bind to HLA-A2 and an 11-mer protein transduction epitope known to enhance peptide loading and antigen presentation.
- Patients will receive donor-derived dendritic cell vaccines every 14 days for 6 doses. Donor leukocyte infusions (DLI) will also be administered with the vaccine.
- Study endpoints will include toxicity, feasibility, antigen-specific immunity, and disease response.
- This is an exploratory pilot trial. Up to 12 patients will be treated.
- Stopping rules will take effect if excessive toxicity (e.g., GVHD) or inability to generate vaccines are observed.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||10 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Pilot Trial of WT1 Peptide-Loaded Allogeneic Dendritic Cell Vaccine and Donor Lymphocyte Infusion for WT1-Expressing Hematologic Malignancies|
|Actual Study Start Date :||February 22, 2008|
|Actual Primary Completion Date :||October 18, 2013|
|Actual Study Completion Date :||November 15, 2016|
Related and unrelated donors undergo lymphapheresis to prepare cellular vaccines and to donate lymphocytes for infusion.
Drug: Donor Lymphocytes
Lymphocytes from donors (related or unrelated) collected via lymphapheresis.Drug: Diphenhydramine
Other Name: BenadrylDrug: Acetaminophen
Other Name: Tylenol
Participants receive donor lymphocytes and vaccines prepared from donors.
Drug: WT1 Peptide-Pulsed Dendritic Cells
Other Name: Wilm's Tumor 1Drug: Donor Lymphocytes
Lymphocytes from donors (related or unrelated) collected via lymphapheresis.Drug: IL-4
water-soluble protein; this study will use GMCSF (granulocyte macrophage colony stimulating factor)/IL-4 generated monocyte derived dendritic cells
Other Name: Interleukin-4Drug: KLH
Neoantigen known to induce helper responses; will be used concurrently as a vaccine adjuvant and control antigen.
Other Name: keyhole limpet hemocyaninDrug: WT1 Peptides
dendritic cell vaccineDrug: Endotoxin
Purified lipopolysaccharide prepared from E.Coli 0:113Drug: Diphenhydramine
Other Name: BenadrylDrug: Acetaminophen
Other Name: Tylenol
- Toxicity [ Time Frame: 21 months ]Here is the number of participants with adverse events. For details of the adverse events, see the adverse event module.
- Number of Participants With Graft Versus Host Disease (GVHD) Greater Than or Equal to Grade 3 [ Time Frame: 28 days following completion of last vaccine and/or DLI (donor lymphocyte infusion) administration ]Acute Graft versus Host Disease (GVHD) was graded by the modified Glucksberg scale. 0 = no GVHD normal, 4 = severe GVHD.
- Time to Immune Response [ Time Frame: 4 to 12 weeks ]Immune response was monitored by use of interferon gamma Enzyme-Linked Immunospot (ELISpot) and by delayed-type hypersensitivity (DTH) testing.
- Wilm's Tumor 1 (WT1) Enzyme-Linked Immunospot (ELISpot) [ Time Frame: 48 to 72 hours after placement ]WT1 expression of the hematologic malignancy was confirmed by either having greater than 15% of malignant cells react with anti-WT1 by immunohistochemistry or by having a positive quantitative reverse transcription polymerase chain reaction (RT-PCR) of WT1 compared with a negative control.
- Wilm's Tumor (WT1) Delayed-type Hypersensitivity (DTH) [ Time Frame: 48 to 72 hours after placement ]WT1 expression of the hematologic malignancy was confirmed by either having greater than 15% of malignant cells react with anti-WT1 by immunohistochemistry or by having a positive quantitative reverse transcription polymerase chain reaction (RT-PCR) of WT1 compared with a negative control. DTH skin testing was performed using KLH and with a cocktail of WT1 peptides as 2 separate injections. Enzyme-Linked Immunospot (ELISpot) was performed against each peptide and was considered positive if results were at least 10 spots above background on at least 2 measurements. DTH was considered positive if there was at least .5cm induration 48 to 72 hours after placement.
- Keyhole Limpet Hemocyanin (KLH) Delayed-type Hypersensitivity (DTH) [ Time Frame: 48 to 72 hours after placement ]KLH is a neoantigen known to induce helper response was used concurrently as a vaccine adjuvant and control antigen. DTH skin testing was performed using KLH and with a cocktail of WT1 peptides as 2 separate injections. Enzyme-Linked Immunospot (ELISpot) was performed against each peptide and was considered positive if results were at least 10 spots above background on at least 2 measurements. DTH was considered positive if there was at least .5cm induration 48 to 72 hours after placement.
- Number of Participants With Progressive Disease [ Time Frame: 4 to12 weeks ]Progressive disease is at least a 20% increase in the sum of the longest diameter of all target lesions (i.e. tumor response). Response criteria for acute leukemia's is worse marrow classification (i.e., M status) with at least a 50% increase in the percentage of marrow blasts, or no change in marrow classification (i.e., M status), but a 50% or greater increase in absolute peripheral blast count or extent of medullary disease
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00923910
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Terry J Fry, M.D.||National Cancer Institute (NCI)|