Original paperCancer therapySafety and tolerability of allogeneic dendritic cell vaccination with induction of Wilms tumor 1–specific T cells in a pediatric donor and pediatric patient with relapsed leukemia: a case report and review of the literature
Introduction
The outcome of patients with relapsed leukemia after allogeneic hematopoietic stem cell transplantation (HSCT) is discouraging and indicates an urgent need for new therapies [1]. Donor lymphocyte infusion (DLI) has been proposed to overcome leukemic relapse after HSCT by boosting graft-versus-leukemia effect. However, DLI provokes unmanageable graft-versus-host disease (GVHD) because many allogeneic antigens are targeted by donor T cells [2].
Leukemic antigen-specific autologous dendritic cell (DC)-based vaccination for hematological malignancies is currently explored to avoid off-target effects [3], [4]. The autologous DC therapy requires the production of DC vaccines from patient-derived peripheral blood mononuclear cells (PBMCs) through the use of leukapheresis. Although healthy donor-derived PBMCs may be available to generate the allogeneic DC vaccines in the patients who received HSCT, little has been reported on the safety and tolerability of the production and administration of donor-derived DCs for the donor and recipient. Additionally, the induction of leukemic antigen-specific T cells by allogeneic DC vaccines remains unclear.
Thus, we conducted a phase I clinical trial to test the safety and tolerability of Wilms tumor 1 (WT1)-specific allogeneic DC vaccination for pediatric patients with relapsed leukemia after HSCT. We report the results from the first patient who completed the allogeneic DC vaccination.
Section snippets
Patients
This clinical trial (UMIN: 000002105) was approved by the institutional review board of the Shinshu University School of Medicine. Written informed consent was obtained from patients over 12 years of age, HSCT donors and their parents, according to the Helsinki Declaration. Adverse effects were graded by use of the National Cancer Institute's Common Toxicity Criteria version 3.
Preparation of allogeneic DC vaccine
Mature DCs (mDCs) were generated under Good Manufacturing Practice conditions and cryopreserved in liquid nitrogen as
Transplantations and lymphocyte infusions
A 12-year-old girl was diagnosed with B-precursor acute lymphoblastic leukemia. She underwent allogeneic bone marrow transplantation from her mother (HLA 8/8 allele-match) in first complete remission (CR) (first HSCT, Figure 1). The engraftment was successful, but she had a hematological relapse 11 months after this first HSCT. A combination of chemotherapy and two sessions of donor lymphocyte infusion (DLI) did not induce long-term remission. Consequently, she was transplanted with peripheral
Discussion
This study describes the treatment of the youngest donor and recipient for allogeneic DC vaccination. We successfully generated 15 doses of DC vaccine (1 × 107 cells/dose) safely from a 12-year-old, healthy donor, with a single leukapheresis session. The 14 doses of allogeneic DC vaccination pulsed with WT1235–243 peptide were all safe and well tolerated by the 15-year-old patient, without adverse effects except for a grade 2 local reaction. A literature review identified six patients with
Acknowledgments
We wish to thank nurse Kayo Horiuchi for taking care of the patients and harvesting the PBMCs from the HSCT donor. This clinical trial was supported by Management Expense Grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan (grant number: 24501330 and 24791050).
Disclosure of interests: The authors have no commercial, proprietary, or financial interest in the products or companies described in this article.
References (13)
- et al.
Graft-versus-leukemia reactions in allogeneic chimeras
Blood
(2004) - et al.
A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS
Blood
(2009) - et al.
Graft-versus-leukemia effects associated with detectable Wilms tumor-1 specific T lymphocytes after allogeneic stem-cell transplantation for acute lymphoblastic leukemia
Blood
(2007) - et al.
WT1-specific T-cell responses in high-risk multiple myeloma patients undergoing allogeneic T cell-depleted hematopoietic stem cell transplantation and donor lymphocyte infusions
Blood
(2013) - et al.
CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia
Blood
(2002) - et al.
Outcomes and prognostic factors of adults with acute lymphoblastic leukemia who relapse after allogeneic hematopoietic cell transplantation. An analysis on behalf of the Acute Leukemia Working Party of EBMT
Leukemia
(2012)
Cited by (31)
Nanomedicine for improvement of dendritic cell-based cancer immunotherapy
2020, International ImmunopharmacologyDeveloping T-cell therapies for lymphoma without receptor engineering
2017, Blood AdvancesCitation Excerpt :However, this immune-cell–mediated effect is limited, and disease relapse remains the largest cause of HSCT failure. Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) and T/natural killer (NK)–cell lymphoproliferative disorder have all been the focus of cell-mediated therapeutic approaches (Tables 1 and 2).35-60 B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) have been shown to be amenable to T-cell therapy with highly promising results in CD19-CAR T-cell studies.
Hematologic neoplasms: Dendritic cells vaccines in motion
2017, Clinical ImmunologyCitation Excerpt :In this regard, autologous DCs from ALL patients, pulsed with leukemic cell lysates, prompted lymphocytes potentiated against leukemic cells with evident relationships among cytotoxicity levels, lymphocyte subsets, and patients clinical course [126]. Recently, WT1-specific allogeneic DCs vaccination was performed in relapsed leukemia patients with [127]. WT1-tetramer analysis and ELISPOT assay highlighted specific immune responses in patients after vaccination.
Clinical effect and immunological response in patients with advanced malignant glioma treated with WT1-pulsed dendritic cell-based immunotherapy: A report of two cases
2017, Interdisciplinary Neurosurgery: Advanced Techniques and Case ManagementCitation Excerpt :Scheibenbogen et al. observed spontaneous WT1-specific T cell responses in acute myeloid leukemia patients [26]. The response of the WT1-specific CTLs may have been boosted by DC vaccine therapy as described in a relapsed patient with leukemia given allogeneic DC vaccination targeting WT1 [27]. WT1-pulsed DC vaccination may have also enhanced the immunological response in our patients.