scholarly journals Clinical Outcome after Adoptive Infusion of BPX-501 Cells (donor T cells transduced with iC9 suicide gene) in Children with Thalassemia Major (TM) Given Alfa/Beta T-Cell Depleted HLA-Haploidentical Stem Cell Transplantation (HSCT)

2016 ◽  
Vol 22 (3) ◽  
pp. S306 ◽  
Author(s):  
Alice Bertaina ◽  
Barbarella Lucarelli ◽  
Pietro Merli ◽  
Valentina Bertaina ◽  
Valentina Ferruzzi ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Clinical Outcome ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Suicide Gene ◽  
Thalassemia Major ◽  
Haploidentical Stem Cell Transplantation ◽  
Donor T Cells

scholarly journals T-cell suicide gene therapy prompts thymic renewal in adults after hematopoietic stem cell transplantation

Blood ◽  
2012 ◽  
Vol 120 (9) ◽  
pp. 1820-1830 ◽  
Author(s):  
Luca Vago ◽  
Giacomo Oliveira ◽  
Attilio Bondanza ◽  
Maddalena Noviello ◽  
Corrado Soldati ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Suicide Gene ◽  
Hematopoietic Stem ◽  
Donor T Cells

Abstract The genetic modification of T cells with a suicide gene grants a mechanism of control of adverse reactions, allowing safe infusion after partially incompatible hematopoietic stem cell transplantation (HSCT). In the TK007 clinical trial, 22 adults with hematologic malignancies experienced a rapid and sustained immune recovery after T cell–depleted HSCT and serial infusions of purified donor T cells expressing the HSV thymidine kinase suicide gene (TK+ cells). After a first wave of circulating TK+ cells, the majority of T cells supporting long-term immune reconstitution did not carry the suicide gene and displayed high numbers of naive lymphocytes, suggesting the thymus-dependent development of T cells, occurring only upon TK+-cell engraftment. Accordingly, after the infusions, we documented an increase in circulating TCR excision circles and CD31+ recent thymic emigrants and a substantial expansion of the active thymic tissue as shown by chest tomography scans. Interestingly, a peak in the serum level of IL-7 was observed after each infusion of TK+ cells, anticipating the appearance of newly generated T cells. The results of the present study show that the infusion of genetically modified donor T cells after HSCT can drive the recovery of thymic activity in adults, leading to immune reconstitution.

Adoptive Immunotherapy after Haploidentical Stem Cell Transplantation with T Cells Allodepleted by Photodynamic Purging

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1157-1157
Author(s):  
Katia Perruccio ◽  
Fabiana Topini ◽  
Antonella Tosti ◽  
Alessandra Carotti ◽  
Teresa Aloisi ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Adoptive Immunotherapy ◽  
Cell Responses ◽  
Alloreactive T Cells ◽  
Haploidentical Stem Cell Transplantation ◽  
Donor T Cells

Abstract After haploidentical stem cell transplantation, immune recovery is slow due to decaying thymic function and extensive T-cell depletion of the graft which is needed to prevent Graft-versus-Host Disease (GvHD). Consequently, infectious related mortality is about 30–40%. To address this problem, we investigated the efficacy of adoptive immunotherapy after photodynamic purging of alloreactive T cells (ATIR, Kiadis Pharma, Amsterdam, The Netherlands) in preventing GvHD and improving immune reconstitution. The 4,5-dibromorhodamine methyl ester (TH9402) is a photosensitizer structurally similar to rhodamine. When donor T cells are activated with allogeneic cells, they retain TH9402 which becomes highly cytotoxic upon activation with visible light. MLR-activated donor T cells are exposed to a fluorescent-light scanning device to eliminate alloreactive T cells. We designed a protocol which provided 3,260 ± 450 (mean ± SD)-fold allodepletion, full retention of T-regulatory cells, and preservation of pathogen- and leukaemia-specific T-cell responses (against Aspergillus, Candida, Cytomegalovirus (CMV), Adenovirus (ADV), Herpes Simplex Virus (HSV), Varicella Zoster Virus (VZV), Toxoplasma antigens; and against leukaemia cells and leukaemia antigens (WT1 and Ca125)). Optimized protocol conditions are: MLR cell concentration: 3–5 × 10e6/ml; MLR duration: 24 hours; TH9402 concentration: 5 μM; TH9402 incorporation, as measured by median fluorescence index (MFI): 20,000 – 25,000; energy delivery: 0.1 J/cm2. Here we present the preliminary results of a clinical trial. Escalating doses of photodynamically allodeleted donor T cells, i.e., 1.25 × 10e5/Kg, 2.5 × 10e5/Kg, 5 × 10e5/Kg, 1 × 10e6/Kg and 1.25 × 10e6/Kg, were infused into groups of haploidentical transplant recipients. Only 1 patient developed grade III aGvHD at the 1 × 10e6/Kg cell dose and responded to immune suppressive treatment. Immune assessment analyses revealed that infusion of cell doses equal or greater than 5 × 10e5/Kg are associated with significant reconstitution of T-cell counts and appearance of pathogen-specific T-cell responses. One month after infusion, CD4+ and CD8+ T cells were 124 ± 54/cmm and 327 ± 42/cmm (versus 11 ± 4/cmm and 8 ± 4/cmm respectively, in patients receiving T-cell doses below 5 × 10e5/Kg, P = 0.0007). Aspergillus, Candida, CMV, ADV, HSV, VZV, Toxoplasma-specific CD4+ and CD8+ T-cell responses had recovered to frequencies within the normal ranges while they were absent in patients who received T cell doses under 5 × 10e5/Kg (P = 0.0002). In conclusion, this study demonstrates the feasibility, safety and preliminary indications of efficacy of adoptive immunotherapy after photodynamic purging of alloreactive T cells in recipients of haploidentical stem cell transplantation. A larger study will evaluate the impact of these T-cell infusions on transplant related mortality and disease free survival.

scholarly journals Improving Cytomegalovirus-Specific T Cell Reconstitution after Haploidentical Stem Cell Transplantation

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Xiao-Hua Luo ◽  
Ying-Jun Chang ◽  
Xiao-Jun Huang
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Cmv Infection ◽  
Graft Versus Host ◽  
Stem Cell Source ◽  
Haploidentical Stem Cell Transplantation ◽  
Donor T Cells ◽  
Conditioning Regimens

Cytomegalovirus (CMV) infection and delayed immune reconstitution (IR) remain serious obstacles for successful haploidentical stem cell transplantation (haplo-SCT). CMV-specific IR varied according to whether patients received manipulated/unmanipulated grafts or myeloablative/reduced intensity conditioning. CMV infection commonly occurs following impaired IR of T cell and its subsets. Here, we discuss the factors that influence IR based on currently available evidence. Adoptive transfer of donor T cells to improve CMV-specific IR is discussed. One should choose grafts from CMV-positive donors for transplant into CMV-positive recipients (D+/R+) because this will result in better IR than would grafts from CMV-negative donors (D−/R+). Stem cell source and donor age are other important factors. Posttransplant complications, including graft-versus-host disease and CMV infection, as well as their associated treatments, should also be considered. The effects of varying degrees of HLA disparity and conditioning regimens are more controversial. As many of these factors and strategies are considered in the setting of haplo-SCT, it is anticipated that haplo-SCT will continue to advance, further expanding our understanding of IR and CMV infection.

Immune Reconstitution and Immune Correlates of Clinical Outcome IN Acute LEUKEMIA PATIENTS Treated with Haploidentical STEM CELL TRANSPLANTATION.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 46-46
Author(s):  
Alessandra Forcina ◽  
Maddalena Noviello ◽  
Veronica Valtolina ◽  
Attilio Bondanza ◽  
Daniela Clerici ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Patient Specific ◽  
Haploidentical Stem Cell Transplantation ◽  
Gvhd Prophylaxis ◽  
Kinetics Of

Abstract Abstract 46 The broader application of haploidentical stem cell transplantation (haplo-HCT), is limited by the delayed immune reconstitution (IR) secondary to the procedures for GvHD prophylaxis. This ultimately results in a high-rate of infectious complications and non-relapse mortality. We dynamically analyzed immunoreconstitution (IR) in patients undergoing haplo-HCT for acute leukemias enrolled in two different phase I-II clinical trials aimed at improving IR. In the first trial (TK007), 28 patients (out of 50 enrolled) received suicide-gene transduced donor T cells at day +42 after a T-cell depleted graft, in the absence of post-transplant immunosuppression. In the second trial (TrRaMM), 40 patients received an unmanipulated graft and a rapamycin-based GvHD prophylaxis. T-cell immune reconstitution was more rapid in TrRaMM than in TK007 patients, with a threshold of CD3 cells>100/μl reached at days +30 and +90, respectively. In both trials IR was mainly composed of Th1/Tc1 lymphocytes with an inverted CD4/CD8 ratio. While in TrRaMM patients we observed an early expansion of naïve and central memory T cells, producing high amounts of IL-2, in TK patients IR was mainly composed of activated effectors. Furthermore, in TrRaMM patients we detected high levels of CD4+CD25+CD127- T regulatory cells (up to 15% of circulating T lymphocytes) that persisted after rapamycin withdrawal, and was significantly superior to that observed in TK patients and in healthy controls. Interestingly, in contrast to the different kinetics of T-cell reconstitution, no differences were observed in time required to gain protective levels of CMV-specific T cells, as shown by ψIFN ELISPOT analysis. Protective frequencies of CMV-specific lymphocytes were observed 3 months after HCT in both groups, a time-point that in TrRaMM patients corresponds to the average time of rapamycin withdrawal. In both trials the number of circulating CMV-specific T cells was inversely correlated to the number and severity of subsequent CMV reactivations and days of antiviral therapy. GvHD was diagnosed in 16 TrRaMM patients (40%) and in 10 TK patients (35% of patients who received TK cells). Severity of GvHD was different in the two cohort of patients with 5 TrRaMM patients (12,5%) and only 2 TK patients (7%) with grade III-IV GvHD. Of interest, in the TrRaMM group CMV-specific immunity was significantly hampered by the immunosuppressive treatment required to treat GvHD. On the contrary, in the TK group, the administration of ganciclovir was able to activate the suicide machinery and control GvHD without impairing viral-specific T-cell immunocompetence. These results matched with the kinetics of CMV reactivations. We observed that while in TrRaMM patients 80% of viral reactivations occurred after the immunosuppressive therapy, in TK patients no significant differences could be assessed before and after therapy. IFN-ψ ELISPOT might thus be a relevant and predictive test to guide patient-specific clinical monitoring and antiviral treatment. Overall, these results show that early immune reconstitution can be promoted in haplo-HCT by different strategies associated with a wide range of alloreactive potential. The risks and benefits associated with alloreactivity should guide the therapeutic choice tuned on patient disease status and co-morbidities. Disclosures: Bordignon: Molmed Spa: Employment.

scholarly journals C-10. Inducible Caspase-9 Suicide Gene Controls Adverse Effects from Alloreplete T Cells after Haploidentical Stem Cell Transplantation

2015 ◽  
Vol 23 ◽  
pp. S103
Author(s):  
Xiaoou Zhou ◽  
Gianpietro Dotti ◽  
Robert A. Krance ◽  
Caridad Martinez ◽  
Rammurti T. Kamble ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Adverse Effects ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Suicide Gene ◽  
Caspase 9 ◽  
Haploidentical Stem Cell Transplantation

scholarly journals NK Cell Reconstitution in Paediatric Leukemic Patients after T-Cell-Depleted HLA-Haploidentical Haematopoietic Stem Cell Transplantation Followed by the Reinfusion of iCasp9-Modified Donor T Cells

2019 ◽  
Vol 8 (11) ◽  
pp. 1904 ◽  
Author(s):  
Helena Stabile ◽  
Paolo Nisti ◽  
Cinzia Fionda ◽  
Daria Pagliara ◽  
Stefania Gaspari ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Nk Cells ◽  
Cell Transplantation ◽  
Nk Cell ◽  
Haematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Donor T Cells

T-cell-depleted (TCD) human leukocyte antigen (HLA) haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) (TCD-haplo-HSCT) has had a huge impact on the treatment of many haematological diseases. The adoptive transfer of a titrated number of T cells genetically modified with a gene suicide can improve immune reconstitution and represents an interesting strategy to enhance the success of haplo-HSCT. Natural killer (NK) cells are the first donor-derived lymphocyte population to reconstitute following transplantation, and play a pivotal role in mediating graft-versus-leukaemia (GvL). We recently described a CD56lowCD16low NK cell subset that mediates both cytotoxic activity and cytokine production. Given the multifunctional properties of this subset, we studied its functional recovery in a cohort of children given α/βT-cell-depleted haplo-HSCT followed by the infusion of a titrated number of iCasp-9-modified T cells (iCasp-9 HSCT). The data obtained indicate that multifunctional CD56lowCD16low NK cell frequency is similar to that of healthy donors (HD) at all time points analysed, showing enrichment in the bone marrow (BM). Interestingly, with regard to functional acquisition, we identified two groups of patients, namely those whose NK cells did (responder) or did not (non responder) degranulate or produce cytokines. Moreover, in patients analysed for both functions, we observed that the acquisition of degranulation capacity was not associated with the ability to produce interferon-gamma (IFN-γ Intriguingly, we found a higher BM and peripheral blood (PB) frequency of iCas9 donor T cells only in patients characterized by the ability of CD56lowCD16low NK cells to degranulate. Collectively, these findings suggest that donor iCasp9-T lymphocytes do not have a significant influence on NK cell reconstitution, even if they may positively affect the acquisition of target-induced degranulation of CD56lowCD16low NK cells in the T-cell-depleted haplo-HSC transplanted patients.

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