Publications by authors named "Valentina Bertaina"

12 Publications

  • Page 1 of 1

HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia.

Blood Adv 2021 Mar;5(5):1333-1339

Department of Pediatric Hemato-Oncology and Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS) Bambino Gesù Children's Hospital, Rome, Italy.

We report on the outcome of 24 patients with Fanconi anemia (FA) lacking an HLA matched related or unrelated donor, given an HLA-haploidentical T-cell receptor αβ (TCRαβ+) and CD19+ cell-depleted hematopoietic stem cell transplantation (HSCT) in the context of a prospective, single-center phase 2 trial. Sustained primary engraftment was achieved in 22 (91.6%) of 24 patients, with median time to neutrophil recovery of 12 days (range, 9-15 days) and platelet recovery of 10 days (range, 7-14 days). Cumulative incidences of grade 1 to 2 acute graft-versus-host disease (GVHD) and chronic GVHD were 17.4% (95% confidence interval [CI], 5.5%-35.5%) and 5.5% (95% CI, 0.8%-33.4%), respectively. The conditioning regimen, which included fludarabine, low-dose cyclophosphamide and, in most patients, single-dose irradiation was well tolerated; no fatal transplant-related toxicity was observed. With a median follow-up of 5.2 years (range, 0.3-8.7 years), the overall and event-free survival probabilities were 100% and 86.3% (95% CI, 62.8%-95.4%), respectively (2 graft failures and 1 case of poor graft function were considered as events). The 2 patients who experienced primary graft failure underwent a subsequent successful HSCT from the other parent. This is the first report of FA patients given TCRαβ+/CD19+-depleted haplo-HSCT in the context of a prospective trial, and the largest series of T-cell-depleted haplo-HSCT in FA reported to date. This trial was registered at www.clinicaltrials.gov as #NCT01810120.
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http://dx.doi.org/10.1182/bloodadvances.2020003707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948273PMC
March 2021

Immune Modulation Properties of Zoledronic Acid on TcRγδ T-Lymphocytes After TcRαβ/CD19-Depleted Haploidentical Stem Cell Transplantation: An analysis on 46 Pediatric Patients Affected by Acute Leukemia.

Front Immunol 2020 12;11:699. Epub 2020 May 12.

Department of Pediatric Hematology and Oncology and of Cell and Gene Therapy, Scientific Institute for Research and Healthcare (IRCCS), Bambino Gesù Childrens' Hospital, Rome, Italy.

TcRαβ/CD19-cell depleted HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a promising new platform for children affected by acute leukemia in need of an allograft and lacking a matched donor, disease recurrence being the main cause of treatment failure. The use of zoledronic acid to enhance TcRγδ+ lymphocyte function after TcRαβ/CD19-cell depleted haplo-HSCT was tested in an open-label, feasibility, proof-of-principle study. Forty-six children affected by high-risk acute leukemia underwent haplo-HSCT after removal of TcRαβ+ and CD19+ B lymphocytes. No post-transplant pharmacological graft-versus-host disease (GvHD) prophylaxis was given. Zoledronic acid was administered monthly at a dose of 0.05 mg/kg/dose (maximum dose 4 mg), starting from day +20 after transplantation. A total of 139 infusions were administered, with a mean of 3 infusions per patient. No severe adverse event was observed. Common side effects were represented by asymptomatic hypocalcemia and acute phase reactions (including fever, chills, malaise, and/or arthralgia) within 24-48 h from zoledronic acid infusion. The cumulative incidence of acute and chronic GvHD was 17.3% (all grade I-II) and 4.8% (all limited), respectively. Patients given 3 or more infusions of zoledronic acid had a lower incidence of both acute GvHD (8.8 vs. 41.6%, = 0.015) and chronic GvHD (0 vs. 22.2%, = 0.006). Transplant-related mortality (TRM) and relapse incidence at 3 years were 4.3 and 30.4%, respectively. Patients receiving repeated infusions of zoledronic acid had a lower TRM as compared to those receiving 1 or 2 administration of the drug (0 vs. 16.7%, = 0.01). Five-year overall survival (OS) and disease-free survival (DFS) for the whole cohort were 67.2 and 65.2%, respectively, with a trend toward a better OS for patients receiving 3 or more infusions (73.1 vs. 50.0%, = 0.05). The probability of GvHD/relapse-free survival was significantly worse in patients receiving 1-2 infusions of zoledonic acid than in those given ≥3 infusions (33.3 vs. 70.6%, respectively, = 0.006). Multivariable analysis showed an independent positive effect on outcome given by repeated infusions of zoledronic acid (HR 0.27, = 0.03). These data indicate that the use of zoledronic acid after TcRαβ/CD19-cell depleted haploHSCT is safe and may result in a lower incidence of acute GvHD, chronic GvHD, and TRM.
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http://dx.doi.org/10.3389/fimmu.2020.00699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235359PMC
March 2021

Unrelated donor vs HLA-haploidentical α/β T-cell- and B-cell-depleted HSCT in children with acute leukemia.

Blood 2018 12 22;132(24):2594-2607. Epub 2018 Oct 22.

Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ospedale Bambino Gesù, Rome, Italy.

Traditionally, hematopoietic stem cell transplantation (HSCT) from both HLA-matched related and unrelated donors (UD) has been used for treating children with acute leukemia (AL) in need of an allograft. Recently, HLA-haploidentical HSCT after αβ T-cell/B-cell depletion (αβhaplo-HSCT) was shown to be effective in single-center studies. Here, we report the first multicenter retrospective analysis of 127 matched UD (MUD), 118 mismatched UD (MMUD), and 98 αβhaplo-HSCT recipients, transplanted between 2010 and 2015, in 13 Italian centers. All these AL children were transplanted in morphological remission after a myeloablative conditioning regimen. Graft failure occurred in 2% each of UD-HSCT and αβhaplo-HSCT groups. In MUD vs MMUD-HSCT recipients, the cumulative incidence of grade II to IV and grade III to IV acute graft-versus-host disease (GVHD) was 35% vs 44% and 6% vs 18%, respectively, compared with 16% and 0% in αβhaplo-HSCT recipients ( < .001). Children treated with αβhaplo-HSCT also had a significantly lower incidence of overall and extensive chronic GVHD ( < .01). Eight (6%) MUD, 32 (28%) MMUD, and 9 (9%) αβhaplo-HSCT patients died of transplant-related complications. With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67%, 55%, and 62%, respectively. In the 3 groups, chronic GVHD-free/relapse-free (GRFS) probability of survival was 61%, 34%, and 58%, respectively ( < .001). When compared with patients given MMUD-HSCT, αβhaplo-HSCT recipients had a lower cumulative incidence of nonrelapse mortality and a better GRFS ( < .001). These data indicate that αβhaplo-HSCT is a suitable therapeutic option for children with AL in need of transplantation, especially when an allele-matched UD is not available.
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http://dx.doi.org/10.1182/blood-2018-07-861575DOI Listing
December 2018

Che-1 is targeted by c-Myc to sustain proliferation in pre-B-cell acute lymphoblastic leukemia.

EMBO Rep 2018 03 24;19(3). Epub 2018 Jan 24.

SAFU, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Regina Elena National Cancer Institute, Rome, Italy

Despite progress in treating B-cell precursor acute lymphoblastic leukemia (BCP-ALL), disease recurrence remains the main cause of treatment failure. New strategies to improve therapeutic outcomes are needed, particularly in high-risk relapsed patients. Che-1/AATF (Che-1) is an RNA polymerase II-binding protein involved in proliferation and tumor survival, but its role in hematological malignancies has not been clarified. Here, we show that Che-1 is overexpressed in pediatric BCP-ALL during disease onset and at relapse, and that its depletion inhibits the proliferation of BCP-ALL cells. Furthermore, we report that c-Myc regulates Che-1 expression by direct binding to its promoter and describe a strict correlation between Che-1 expression and c-Myc expression. RNA-seq analyses upon Che-1 or c-Myc depletion reveal a strong overlap of the respective controlled pathways. Genomewide ChIP-seq experiments suggest that Che-1 acts as a downstream effector of c-Myc. These results identify the pivotal role of Che-1 in the control of BCP-ALL proliferation and present the protein as a possible therapeutic target in children with relapsed BCP-ALL.
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http://dx.doi.org/10.15252/embr.201744871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835840PMC
March 2018

Outcome of children with acute leukemia given HLA-haploidentical HSCT after αβ T-cell and B-cell depletion.

Blood 2017 08 6;130(5):677-685. Epub 2017 Jun 6.

Immunology Research Area, IRCCS Ospedale Bambino Gesù, Rome, Italy.

Allogeneic hematopoietic stem cell transplantation (HSCT) from an HLA-haploidentical relative (haplo-HSCT) is a suitable option for children with acute leukemia (AL) either relapsed or at high-risk of treatment failure. We developed a novel method of graft manipulation based on negative depletion of αβ T and B cells and conducted a prospective trial evaluating the outcome of children with AL transplanted with this approach. Eighty AL children, transplanted between September 2011 and September 2014, were enrolled in the trial. All children were given a fully myeloablative preparative regimen. Anti-T-lymphocyte globulin from day -5 to -3 was used for preventing graft rejection and graft-versus-host disease (GVHD); no patient received any posttransplantation GVHD prophylaxis. Two children experienced primary graft failure. The cumulative incidence of skin-only, grade 1-2 acute GVHD was 30%; no patient developed extensive chronic GVHD. Four patients died, the cumulative incidence of nonrelapse mortality being 5%, whereas 19 relapsed, resulting in a 24% cumulative incidence of relapse. With a median follow-up of 46 months for surviving patients, the 5-year probability of chronic GVHD-free, relapse-free survival (GRFS) is 71%. Total body irradiation-containing preparative regimen was the only variable favorably influencing relapse incidence and GRFS. The outcomes of these 80 patients are comparable to those of 41 and 51 children given transplantation from an HLA-identical sibling or a 10/10 allelic-matched unrelated donor in the same period. These data indicate that haplo-HSCT after αβ T- and B-cell depletion represents a competitive alternative for children with AL in need of urgent allograft. This trial was registered at www.clinicaltrials.gov as #NCT01810120.
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http://dx.doi.org/10.1182/blood-2017-04-779769DOI Listing
August 2017

Preservation of Antigen-Specific Functions of αβ T Cells and B Cells Removed from Hematopoietic Stem Cell Transplants Suggests Their Use As an Alternative Cell Source for Advanced Manipulation and Adoptive Immunotherapy.

Front Immunol 2017 23;8:332. Epub 2017 Mar 23.

Department of Pediatric Hematology and Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy; Department of Pediatrics, University of Pavia, Pavia, Italy.

Hematopoietic stem cell transplantation is standard therapy for numerous hematological diseases. The use of haploidentical donors, sharing half of the HLA alleles with the recipient, has facilitated the use of this procedure as patients can rely on availability of a haploidentical donor within their family. Since HLA disparity increases the risk of graft-versus-host disease, T-cell depletion has been used to remove alloreactive lymphocytes from the graft. Selective removal of αβ T cells, which encompass the alloreactive repertoire, combined with removal of B cells to prevent EBV-related lymphoproliferative disease, proved safe and effective in clinical studies. Depleted αβ T cells and B cells are generally discarded as by-products. Considering the possible use of donor T cells for donor lymphocyte infusions or for generation of pathogen-specific T cells as mediators of graft-versus-infection effect, we tested whether cells in the discarded fractions were functionally intact. Response to alloantigens and to viral antigens comparable to that of unmanipulated cells indicated a functional integrity of αβ T cells, in spite of the manipulation used for their depletion. Furthermore, B cells proved to be efficient antigen-presenting cells, indicating that antigen uptake, processing, and presentation were fully preserved. Therefore, we propose that separated αβ T lymphocytes could be employed for obtaining pathogen-specific T cells, applying available methods for positive selection, which eventually leads to indirect allodepletion. In addition, these functional T cells could undergo additional manipulation, such as direct allodepletion or genetic modification.
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http://dx.doi.org/10.3389/fimmu.2017.00332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362590PMC
March 2017

The combination of bortezomib with chemotherapy to treat relapsed/refractory acute lymphoblastic leukaemia of childhood.

Br J Haematol 2017 02 24;176(4):629-636. Epub 2017 Jan 24.

Department of Paediatric Haematology-Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.

Achieving complete remission (CR) in childhood relapsed/refractory acute lymphoblastic leukaemia (ALL) is a difficult task. Bortezomib, a proteasome inhibitor, has in vitro activity against ALL blasts. A phase I-II trial, reported by the Therapeutic Advances in Childhood Leukaemia and Lymphoma (TACL) consortium, demonstrated that bortezomib with chemotherapy has acceptable toxicity and remarkable activity in patients with relapsed ALL failing 2-3 previous regimens. We evaluated bortezomib in combination with chemotherapy in 30 and 7 children with B-cell precursor (BCP) and T-cell ALL, respectively. Bortezomib (1·3 mg/m /dose) was administered intravenously on days 1, 4, 8, and 11. Chemotherapy agents were the same as those used in the TACL trial, consisting of dexamethasone, doxorubicin, vincristine and pegylated asparaginase. Three patients (8·1%) died due to infections. Twenty-seven patients (72·9%) achieved CR or CR with incomplete platelet recovery (CRp). Fourteen had minimal residual disease (MRD) lower than 0·1%. Twenty-two of 30 BCP-ALL patients (73·3%) and 5/7 patients (71%) with T-cell ALL achieved CR/CRp. The 2-year overall survival (OS) is 31·3%; CR/CRp patients with an MRD response had a remarkable 2-year OS of 68·4%. These data confirm that the combination of bortezomib with chemotherapy is a suitable/effective option for childhood relapsed/refractory ALL.
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http://dx.doi.org/10.1111/bjh.14505DOI Listing
February 2017

Cytomegalovirus in hematopoietic stem cell transplant recipients - management of infection.

Expert Rev Hematol 2016 Nov 11;9(11):1093-1105. Epub 2016 Oct 11.

a Dipartimento di Oncoematologia Pediatrica , IRCSS Ospedale Pediatrico Bambino Gesù , Rome , Italy.

Introduction: Cytomegalovirus (CMV) still causes significant morbidity and mortality in patients given allogeneic hematopoietic stem cell transplantation (HSCT). Despite effective pharmacotherapy, potentially life-threatening CMV disease occurs nowadays in up to 10% of HSCT recipients; moreover, routinely used anti-CMV agents have been shown to be associated with morbidity. Areas covered: This review examines different issues related to diagnosis and management of CMV infection in HSCT recipients, paying particular attention to the monitoring of CMV-specific immune recovery, approaches of adoptive cell therapy and new antiviral drugs. Expert commentary: Despite advances in diagnostic tests and treatment, there is still room for refining management of CMV in HSCT recipients. Immunological monitoring should be associated in the future to virological monitoring. The safety profile and efficacy of new anti-CMV agents should be compared with that of standard-of-care drugs. Donor-derived, pathogen-specific T cells adoptively transferred after transplantation could contribute to reduce the impact of CMV infection on patient's outcome.
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http://dx.doi.org/10.1080/17474086.2016.1242406DOI Listing
November 2016

IDO1 involvement in mTOR pathway: a molecular mechanism of resistance to mTOR targeting in medulloblastoma.

Oncotarget 2016 Aug;7(33):52900-52911

Department of Hematology/Oncology and Stem Cell Transplantation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Medulloblastoma (MB) is the most common malignant brain tumor in children. Despite therapeutic advancements, high-risk groups still present significant mortality. A deeper knowledge of the signaling pathways contributing to MB formation and aggressiveness would help develop new successful therapies. The target of rapamycin, mTOR signaling, is known to be involved in MB and is already targetable in the clinical setting. Furthermore, mTOR is a master metabolic regulator able to control cell growth versus autophagy decisions in conditions of amino-acid deprivation that can be due to IDO1 enzymatic activity. IDO1 has been also implicated in the regulation of inflammation, as well as of T cell-mediated immune responses, in a variety of pathological conditions, including brain tumors. In particular, IDO1 induces expansion of regulatory T-cells (Treg), preventing immune response against tumor cells. Analysis of 27 MB tissue specimens for the expression of both mTOR and IDO1 showed their widespread expression in all samples. Testing their cooperation in vitro, a significant involvement of IDO1 in mTOR immunogenic pathway was found, able to counteract the aim of rapamycin treatment. In MB cell lines, inhibition of mTOR strongly induced IDO1 expression and activity, corroborating its ability to recruit Treg cells in the tumor microenvironment. The mTOR/IDO1 cross talk was found to be strictly specific of MB cells. We demonstrated that mTOR pathway cross talks with IDO1 pathway to promote MB immune escape, possibly contributing to failure of mTOR- targeted therapy.
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http://dx.doi.org/10.18632/oncotarget.9284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288157PMC
August 2016

Strategies to accelerate immune recovery after allogeneic hematopoietic stem cell transplantation.

Expert Rev Clin Immunol 2016 11;12(3):343-58. Epub 2015 Dec 11.

a Department of Pediatric Hematology-Oncology , IRCCS, Bambino Gesù Children's Hospital , Rome , Italy.

The interplay existing between immune reconstitution and patient outcome has been extensively demonstrated in allogeneic hematopoietic stem cell transplantation. One of the leading causes of infection-related mortality is the slow recovery of T-cell immunity due to the conditioning regimen and/or age-related thymus damage, poor naïve T-cell output, and restricted T-cell receptor (TCR) repertoires. With the aim of improving posttransplantation immune reconstitution, several immunotherapy approaches have been explored. Donor leukocyte infusions are widely used to accelerate immune recovery, but they carry the risk of provoking graft-versus-host disease. This review will focus on sophisticated strategies of thymus function-recovery, adoptive infusion of donor-derived, allodepleted T cells, T-cell lines/clones specific for life-threatening pathogens, regulatory T cells, and of T cells transduced with suicide genes.
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http://dx.doi.org/10.1586/1744666X.2016.1123091DOI Listing
December 2016

Mobilization of healthy donors with plerixafor affects the cellular composition of T-cell receptor (TCR)-αβ/CD19-depleted haploidentical stem cell grafts.

J Transl Med 2014 Sep 2;12:240. Epub 2014 Sep 2.

Department of Pediatric Hematology/Oncology and Transfusion Medicine, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

Background: HLA-haploidentical hematopoietic stem cell transplantation (HSCT) is suitable for patients lacking related or unrelated HLA-matched donors. Herein, we investigated whether plerixafor (MZ), as an adjunct to G-CSF, facilitated the collection of mega-doses of hematopoietic stem cells (HSC) for TCR-αβ/CD19-depleted haploidentical HSCT, and how this agent affects the cellular graft composition.

Methods: Ninety healthy donors were evaluated. Single-dose MZ was given to 30 'poor mobilizers' (PM) failing to attain ≥40 CD34+ HSCs/μL after 4 daily G-CSF doses and/or with predicted apheresis yields ≤12.0x106 CD34+ cells/kg recipient's body weight.

Results: MZ significantly increased CD34+ counts in PM. Naïve/memory T and B cells, as well as natural killer (NK) cells, myeloid/plasmacytoid dendritic cells (DCs), were unchanged compared with baseline. MZ did not further promote the G-CSF-induced mobilization of CD16+ monocytes and the down-regulation of IFN-γ production by T cells. HSC grafts harvested after G-CSF + MZ were enriched in myeloid and plasmacytoid DCs, but contained low numbers of pro-inflammatory 6-sulfo-LacNAc+ (Slan)-DCs. Finally, children transplanted with G-CSF + MZ-mobilized grafts received greater numbers of monocytes, myeloid and plasmacytoid DCs, but lower numbers of NK cells, NK-like T cells and Slan-DCs.

Conclusions: MZ facilitates the collection of mega-doses of CD34+ HSCs for haploidentical HSCT, while affecting graft composition.
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http://dx.doi.org/10.1186/s12967-014-0240-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4158047PMC
September 2014

Indoleamine 2,3-dioxygenase 1 (IDO1) activity in leukemia blasts correlates with poor outcome in childhood acute myeloid leukemia.

Oncotarget 2014 Apr;5(8):2052-64

Department of Pediatric Hematology/Oncology and Transfusion Medicine, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

Microenvironmental factors contribute to the immune dysfunction characterizing acute myeloid leukemia (AML). Indoleamine 2,3-dioxygenase 1 (IDO1) is an interferon (IFN)-γ-inducible enzyme that degrades tryptophan into kynurenine, which, in turn, inhibits effector T cells and promotes regulatory T-cell (Treg) differentiation. It is presently unknown whether childhood AML cells express IDO1 and whether IDO1 activity correlates with patient outcome. We investigated IDO1 expression and function in 37 children with newly diagnosed AML other than acute promyelocytic leukemia. Blast cells were cultured with exogenous IFN-γ for 24 hours, followed by the measurement of kynurenine production and tryptophan consumption. No constitutive expression of IDO1 protein was detected in blast cells from the 37 AML samples herein tested. Conversely, 19 out of 37 (51%) AML samples up-regulated functional IDO1 protein in response to IFN-γ. The inability to express IDO1 by the remaining 18 AML samples was not apparently due to a defective IFN-γ signaling circuitry, as suggested by the measurement of signal transducer and activator of transcription 3 (STAT3) phosphorylation. Co-immunoprecipitation assays indicated the occurrence of physical interactions between STAT3 and IDO1 in AML blasts. In line with this finding, STAT3 inhibitors abrogated IDO1 function in AML blasts. Interestingly, levels of IFN-γ were significantly higher in the bone marrow fluid of IDO-expressing compared with IDO-nonexpressing AMLs. In mixed tumor lymphocyte cultures (MTLC), IDO-expressing AML blasts blunted the ability of allogeneic naïve T cells to produce IFN-γ and promoted Treg differentiation. From a clinical perspective, the 8-year event-free survival was significantly worse in IDO-expressing children (16.4%, SE 9.8) as compared with IDO-nonexpressing ones (48.0%, SE 12.1; p=0.035). These data indicate that IDO1 expression by leukemia blasts negatively affects the prognosis of childhood AML. Moreover, they speak in favor of the hypothesis that IDO can be targeted, in adjunct to current chemotherapy approaches, to improve the clinical outcome of children with AML.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039144PMC
http://dx.doi.org/10.18632/oncotarget.1504DOI Listing
April 2014