Wilm's Tumor 1 Protein Vaccine to Treat Cancers of the Blood

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 infusions (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 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.

- INCLUSION CRITERIA:

Inclusion Criteria: Patient (i.e., transplant recipient)

Age greater than 1 year and less than 75 years.

One of the following WT1-expressing hematologic malignancies:

1. Acute lymphocytic leukemia (ALL), less than or equal to 25 percent marrow blasts.

2. Acute myelogenous leukemia (AML), less than or equal to 25 percent marrow blasts.

3. Chronic myelogenous leukemia (CML).

- Chronic phase, recurrent after or resistant to DLI or resistant to available abl
kinase inhibitors

- Accelerated phase, less than 20 percent marrow blasts

- Blastic phase, less than or equal to 25 percent marrow blasts

4. Myelodysplastic syndrome (MDS), less than 20 percent marrow blasts.

5. Non-Hodgkin's lymphoma (NHL), stage 4, less than or equal to 25 percent marrow
blasts.

6. Hodgkin's lymphoma (HL)

7. There will be no restriction on the volume of extramedullary disease, with the
exceptions of exclusions for central nervous system involvement or progression deemed
unacceptably rapid.

WT1 expression will be confirmed by at least one of the following criteria:

- Greater than 15 percent of malignant cells react with anti-WT1 by
immunohistochemistry.

- Positive quantitative RT-PCR of WT1 compared with a negative control.

HLA-A2 plus (heterozygous expression is acceptable).

Prior SCT: Prior HLA-matched (5-6/6 antigen or 8-10/10 allele) related or unrelated
allogeneic SCT required. Must be at least 42 days post-transplant, have had recovery
of transplant-associated toxicity to less than grade 2, and have post-transplant
donor engraftment as defined by donor chimerism greater than 50 percent (peripheral
blood), neutrophil recovery to an ANC greater than 500/microl independent of myeloid
growth factors, and platelet recovery to greater than 20,000/microL independent of
transfusion.

Disease status: Post-transplant residual or relapsed disease. Minimal residual
disease (MRD) by PCR or flow cytometry is acceptable in accordance with standard
disease-specific diagnostic criteria.

Availability of previous allogeneic donor to donate cells again.

Prior therapy: Disease-specific therapy must be stopped at least 14 days prior to
protocol Cycle 1 Day 1 (C1D1) and recovery of treatment-associated toxicity to
greater than grade 2 is required prior to initiation of protocol therapy. Patients
may have received prior DLI, but the last dose must be at least 28 days prior to C1D1
and there must be no active GVHD greater than grade 1 acute or extensive chronic.
Systemic immunosuppression must be stopped at least 28 days prior to protocol C1D1
and there must be no active GVHD greater than grade 1 acute or extensive chronic.
There is no time restriction in regard to prior intrathecal chemotherapy provided
there is complete recovery from any acute toxic effects of such. Patients receiving
hydroxyurea are allowed.

Performance status of 0, 1, 2, or 3.

Renal function: Patients must have a serum creatinine less than or equal to 1.5 times
the upper limit of normal based on age-specific normal range OR a creatinine
clearance greater than or equal to 60 mL/min/1.73 m(2).

Hepatic function: Patients must have a total bilirubin less than or equal to 2.0
mg/dl and ALT less than or equal to 5 times the upper limit of normal based on age-
specific normal ranges.

Ability to give informed consent. For patients less than 18 years of age, their legal
guardian must give informed consent. Pediatric patients will be included in age
appropriate discussion in order to obtain verbal assent.

Recipients of unrelated donor transplants must sign a release of information form to
authorize NMDP transfer of information to the NIH.

Subjects of childbearing or child-fathering potential must be willing to use a
medically acceptable form of birth control, which includes abstinence, while they are
being treated on this study.

Inclusion Criteria: Donor

Weight greater than or equal to 18 kg, and for unrelated donors only age greater than
or equal to 18 years

Previous HLA-matched related or unrelated allogeneic donor. Donors must be 5-6/6
antigen or 8-10/10 allele matched.

HLA-A2 plus (heterozygous expression is acceptable).

Adequate venous access for peripheral apheresis, or consent to use a temporary
central venous catheter for apheresis.

Donor selection will be in accordance with NIH/CC Department of Transfusion Medicine
(DTM) criteria and, in the case of an unrelated donor, the National Marrow Donor
Program (NMDP) standards. When a potentially eligible recipient of an unrelated donor
product is identified, the recipient will complete an NMDP search transfer request to
allow NIH NMDP staff to contact the NMDP Coordinating Center, who will, in turn,
contact the donor's prior Donor Center. The NMDP Policy for Subsequent Donation
Requests will be followed and the appropriate forms (Subsequent Donation Request form
and Therapeutic T Cell Collection Prescription) will be submitted as required.

Ability to give informed consent. For donors less than 18 years of age, their legal
guardian must give informed consent. Pediatric donors must give verbal assent and be
cleared by social work and a mental health specialist to participate.

EXCLUSION CRITERIA:

Exclusion Criteria: Patient

Active GVHD greater than grade 1 acute or extensive chronic.

Breast feeding or pregnant females (due to risk to fetus or newborn).

Central nervous system (CNS) malignancy by any of the following criteria:

- Demonstration of malignant cells in the cerebrospinal fluid (CSF) in patients
with leukemia or MDS as manifested by CSF WBC greater than 5/microL and
confirmation of CSF blasts.

- Cranial neuropathies deemed secondary to the underlying malignancy.

- CNS mass lesions deemed secondary to the underlying malignancy.

- NB: History of CNS involvement without current evidence of CNS malignancy is NOT
an exclusion.

Rapidly progressive malignancy and/or clinically significant systemic illness (e.g.,
severe unstable infections or organ dysfunction) that in the judgment of the PI would
likely compromise the patient's ability to tolerate this therapy or interfere with
the study procedures, including but not limited to a life expectancy of less than 3
months.

High risk of inability to comply with protocol requirements as determined by
principal investigator, social work, and primary team.

HIV infection or HTLV-1 infection (due to associated immune suppression and decreased
likelihood of developing an immune response to the vaccine and increased risk of
severe infection).

Active hepatitis B or C infection as defined by seropositive for hepatitis B (HbSAg)
or hepatitis C and elevated liver transaminases.

Corticosteroids (dexamethasone equivalent up to 0.1 mg/kg/day) will be permitted.
Topical agents and/or inhaled corticosteroids are permitted.

Exclusion Criteria: Donor

History of medical illness that in the estimation of the PI or DTM/NMDP physician
poses prohibitive risk to donation.

Anemia (Hb less than 10 gm/dl) or thrombocytopenia (less than 100,000/microliter).

Breast feeding or pregnant females (due to risk to fetus or newborn).

High risk of inability to comply with protocol requirements as determined by the
principal investigator and donor center team.

Positive screening test for transfusion-transmissible infection in accordance with
DTM or NMDP donation standards.

Kaposi's sarcoma