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3055 A Pilot Trial of WT1 Peptide-Loaded Allogeneic Dendritic Cell Vaccine and Donor Lymphocyte Infusion for WT1-Expressing Hematologic Malignancies and Post-Transplant Relapse

Program: Oral and Poster Abstracts
Session: 723. Clinical Allogeneic and Autologous Transplantation - Late Complications and Approaches to Disease Recurrence: Poster II
Sunday, December 11, 2011, 6:00 PM-8:00 PM
Hall GH (San Diego Convention Center)

Nirali N Shah, MD1*, David Loeb, MD, PhD2*, Hahn Khuu, MD3*, David Stroncek, MD4, Mark Raffeld, MD5, Cindy Delbrook, RN1*, Kelly Richards, RN1*, Kristin Baird, MD1*, Jason Levine, MD1, Susan F. Leitman, MD4, Crystal L Mackall, MD1, Terry J Fry, MD1 and Alan S Wayne, MD1

1Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
2Oncology, Johns Hopkins University, Baltimore, MD
3Transfusion Medicine, National Institutes of Health, Bethesda, MD
4Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD
5Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD

Background: Treatment of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains challenging. The Wilms' tumor 1 (WT1) gene product is a tumor-associated antigen that is expressed in acute leukemia and other hematologic malignancies with limited expression in normal tissues. This pilot trial incorporates antigen-specific immunotherapy and allogeneic adoptive cell transfer for pediatric and adult patients with relapsed hematologic malignancies after alloHSCT. The primary objectives are to assess safety and feasibility of a peptide-loaded donor-derived dendritic cell (DC) vaccine and donor lymphocyte infusion (DLI) designed to enhance the graft-vs-leukemia effect. Secondary objectives are to determine if immunologic and clinical responses to WT1 specific peptides can be generated by this novel vaccine strategy after alloHSCT.

Design: HLA-A2+ patients with WT1-expressing hematologic malignancies that have relapsed after alloHSCT are eligible. Donor-derived DC vaccines are given every 2 weeks for 6 doses and DLI every 4 weeks for 3 doses. Peripheral blood monocyte-derived DCs are loaded with a combination of three HLA-A2 binding WT1 peptides (WT1 37-45; WT1 126-134; WT1 187-195) linked to the 11-mer HIV TAT protein transduction domain peptide (47-57) designed to enhance antigen presentation. The DCs are generated from donor peripheral blood monocytes that are separated from DLI collected by apheresis. Monocytes are incubated with GM-CSF and IL-4 followed by maturation with LPS and IFN-g. WT1 expression is assessed using immunohistochemistry and/or quantative RT-PCR. Study endpoints included toxicity, feasibility, and antigen-specific immune and clinical responses.

Results: 4 patients, aged 9-19 years have been treated to date, 3 with acute lymphoblastic leukemia (ALL) and one with Hodgkin lymphoma (HL). Donors were matched siblings in 3 cases and a 10/10 HLA matched father in one case. Vaccines were successfully produced from all donors. All patients tolerated vaccine and DLI administrations well. The most common adverse events were mild, reversible pain and pruritus at vaccine administration and delayed type hypersensitivity (DTH) skin test sites. One patient developed Grade I skin GVHD that did not require treatment. Immune responses were observed in all 3 patients with ALL. ELISPOT was considered positive when it was at least two times greater than and had at least 10 spots more than background. 3 of 4 (75%) patients had positive ELISPOT responses to WT1 peptides. 3 of 4 (75%) patients had positive DTH responses to the keyhole limpet hemocyanin (KLH) control and 2 of 4 (50%) to the WT1 peptides. Median overall survival was 12 months. 1 patient remains in remission 12 months after initiation of therapy and 3 have died of disease. All donors tolerated apheresis well and there were no complications from donor procedures.

Conclusions: This novel allogeneic immunotherapy regimen is feasible, well-tolerated and can induce immune responses in the allogeneic setting. Accrual is ongoing.

Table: Summary of DTH and ELISPOT Responses

Patient #

Diagnosis

KLH DTH Response

WT1 DTH Response

WT1 ELISPOT Response

1

ALL

+

+

+

2

HL

-

-

-

3

ALL

+

-

+

4

ALL

+

+

+

Disclosures: No relevant conflicts of interest to declare.

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