Dataset Information

Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.

ABSTRACT: We evaluated HLA-compatible donor leukocyte infusions (DLIs) and HLA-compatible or HLA-disparate EBV-specific T cells (EBV-CTLs) in 49 hematopoietic cell transplantation recipients with biopsy-proven EBV-lymphoproliferative disease (EBV-LPD). DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ? 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EBV-CTLs. The probability of complete response was significantly lower among patients with multiorgan involvement. In responders, DLIs and EBV-CTLs regularly induced exponential increases in EBV-specific CTL precursor (EBV-CTLp) frequencies within 7-14 days, with subsequent clearance of EBV viremia and resolution of disease. In nonresponders, EBV-CTLps did not increase and EBV viremia persisted. Treatment failures were correlated with impaired T-cell recognition of tumor targets. Either donor-derived EBV-CTLs that had been sensitized with autologous BLCLs transformed by EBV strain B95.8 could not lyse spontaneous donor-derived EBV-transformed BLCLs expanded from the patient's blood or biopsied tumor or they failed to lyse their targets because they were selectively restricted by HLA alleles not shared by the EBV-LPD. Therefore, either unselected DLIs or EBV-specific CTLs can eradicate both untreated and Rituxan-resistant lymphomatous EBV-LPD, with failures ascribable to impaired T-cell recognition of tumor-associated viral antigens or their presenting HLA alleles.

SUBMITTER: Doubrovina E

PROVIDER: S-EPMC3311278 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.

Doubrovina Ekaterina E Oflaz-Sozmen Banu B Prockop Susan E SE Kernan Nancy A NA Abramson Sara S Teruya-Feldstein Julie J Hedvat Cyrus C Chou Joanne F JF Heller Glenn G Barker Juliet N JN Boulad Farid F Castro-Malaspina Hugo H George Diane D Jakubowski Ann A Koehne Guenther G Papadopoulos Esperanza B EB Scaradavou Andromachi A Small Trudy N TN Khalaf Ramzi R Young James W JW O'Reilly Richard J RJ

Blood 20111202 11

We evaluated HLA-compatible donor leukocyte infusions (DLIs) and HLA-compatible or HLA-disparate EBV-specific T cells (EBV-CTLs) in 49 hematopoietic cell transplantation recipients with biopsy-proven EBV-lymphoproliferative disease (EBV-LPD). DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ≥ 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EB ...[more]

PMID: 22138512

Similar Datasets

Project description:Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapeutic option for a wide range of immune and hematologic malignant and non-malignant disorders. Once transplanted, allogeneic cells have to support myeloid repopulation and immunological reconstitution, but also need to become tolerant to the host via central or peripheral mechanisms to achieve the desired therapeutic effect. Peripheral tolerance after allogeneic HSCT may be achieved by several mechanisms, though blocking alloreactivity to the host human leukocyte antigens while preserving immune responses to pathogens and tumor antigens remains a challenge. Recently uncovered evidence on the mechanisms of post-HSCT immune reconstitution and tolerance in transplanted patients has allowed for the development of novel cell-based therapeutic approaches. These therapies are aimed at inducing long-term peripheral tolerance and reducing the risk of graft-vs-host disease (GvHD), while sparing the graft-vs-leukemia (GvL) effect. Thus, ensuring effective long term remission in hematologic malignancies. Today, haploidentical stem cell transplants have become a widely used treatment for patients with hematological malignancies. A myriad of ex vivo and in vivo T-cell depletion strategies have been adopted, with the goal of preventing GvHD while preserving GvL in the context of immunogenetic disparity. αβ T-cell/CD19 B-cell depletion techniques, in particular, has gained significant momentum, because of the high rate of leukemia-free survival and the low risk of severe GvHD. Despite progress, better treatments are still needed in a portion of patients to further reduce the incidence of relapse and achieve long-term tolerance. Current post-HSCT cell therapy approaches designed to induce tolerance and minimizing GvHD occurrence include the use of (i) γδ T cells, (ii) regulatory Type 1 T (Tr1) cells, and (iii) engineered FOXP3+ regulatory T cells. Future protocols may include post-HSCT infusion of allogeneic effector or regulatory T cells engineered with a chimeric antigen receptor (CAR). In the present review, we describe the most recent advances in graft engineering and post-HSCT adoptive immunotherapy.

Project description:BACKGROUND:We have recently shown that memory B cells from murine CMV immune donor animals adoptively transferred into immunodeficient mice were highly effective in protecting from a viral infection indicating a therapeutic potential of virus specific memory B cells. These preclinical data provided evidence that a cell-based strategy supporting the humoral immune response might be effective in a clinical setting of immunodeficiency after allogeneic hematopoietic stem cell transplantation. As adoptive transfer of B cells has not been used before in a clinical setting it was necessary to establish a technology for the generation of good manufacturing practice (GMP)-grade B cell products. METHODS:Starting from the leukapheresis product of healthy blood donors, B cells were purified by two different separation strategies using GMP-grade microbeads and the CliniMACS system. A one-step protocol was used for positive enrichment of B lymphocytes with anti-CD19 microbeads. In a two-step enrichment protocol, first T lymphocytes were depleted by anti-CD3 microbeads and the remaining fraction was positively selected by anti-CD19 microbeads. RESULTS:The purity and recovery after enrichment of B lymphocytes from the leukapheresis material in both separations strategies was not statistically different. However, contamination of the B-cell product with T cells was significantly lower after the two-step protocol (0.16%, range 0.01-0.43% after two-step separation and 0.55%, range 0.28-0.85% after one-step separation, p < 0.05). Therefore, a combined CD3 depletion and CD19 enrichment was used for the production of GMP-conform B-cell products from the leukapheresis material of 17 healthy stem cell donors. The absolute B-cell numbers obtained in the final product was 4.70 ± 3.64 × 108 with a purity of 95.98 ± 3.31% B lymphocytes and a recovery of 18.9 ± 10.6%. Importantly, the contamination with CD3+ T cells was extremely low in the final B- cell products (0.10 ± 0.20%). Purified B cells exhibited normal antibody production after in vitro stimulation and showed excellent viability after cryopreservation. CONCLUSIONS:A GMP-grade B-cell product can be obtained with high purity and very low T-cell contamination using the two-step enrichment protocol based on CliniMACS® technology.

Dataset Information

Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.

Publications

Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets