Wilm's Tumor 1 Protein Vaccine to Treat Cancers of the Blood
Condition: Leukemia, Acute Myelogenous (AML); Leukemia, Acute Lymphocytic (ALL); Leukemia, Chronic Myelogenous (CML); Myelodysplastic Syndrome (MDS); Non-Hodgkin's Lymphoma (NHL)
MeSH terms: Lymphoma; Leukemia; Lymphoma, Non-Hodgkin; Preleukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Acute Disease
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

        -  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.

      Objectives:

        -  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.

      Eligibility:

        -  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.

      Design:

        -  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.
    

Detailed description: 
      Background:

        -  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.

      Objectives:

        -  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.

      Eligibility:

        -  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.

      Design:

        -  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.
    

Intervention name(s): WT1 Peptide-Pulsed Dendritic Cells; Donor Lymphocytes; IL-4; KLH; WT1 Peptides; Endotoxin; Diphenhydramine; Acetaminophen
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Lymphocytes from donors (related or unrelated) collected via lymphapheresis.; water-soluble protein; this study will use GMCSF (granulocyte macrophage colony stimulating factor)/IL-4 generated monocyte derived dendritic cells; Neoantigen known to induce helper responses; will be used concurrently as a vaccine adjuvant and control antigen.; dendritic cell vaccine; Purified lipopolysaccharide prepared from E.Coli 0:113; Pre-medication; Pre-medication
Other intervention name(s): Wilm's Tumor 1; Interleukin-4; keyhole limpet hemocyanin; Benadryl; Tylenol
Intervention MeSH terms: Acetaminophen; Diphenhydramine; Promethazine; Interleukin-4; Keyhole-limpet hemocyanin
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: WT1 Peptide Dendritic Cell Vaccine; Hematologic Malignancies; Relapse After Allogeneic Stem Cell Transplantation; Donor Lymphocyte Infusions; WT1-Positive; Dendritic Cell Vaccine; Tumor Immunotherapy; Allogeneic Adoptive Immunotherapy; Hodgkins Lymphoma; Leukemia; Acute Myelogenous Leukemia; AML; Acute Lymphocytic Leukemia; ALL; Chronic Myelogenous Leukemia; CML; Myelodysplasia Syndrome; Non-Hodgkin Lymphoma