UM171-Expanded Cord Blood Transplants Support Robust T-Cell Reconstitution with Low Rates of Severe Infections

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-37
Author(s):  
Maude Dumont-Lagacé ◽  
Qi Li ◽  
Mégane Tanguay ◽  
Jalila Chagraoui ◽  
Tibila Kientega ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Cord Blood ◽  
Immune Reconstitution ◽  
Post Transplant ◽  
T Cell Reconstitution ◽  
Significant Difference ◽  
Severe Infections ◽  
Related Mortality

Introduction Rapid T cell reconstitution following hematopoietic stem cell transplantation is essential for protection against infections and has been associated with lower incidence of chronic graft-vs-host disease (cGVHD), relapse and transplant-related mortality (TRM). While cord blood (CB) transplants are associated with lower rates of cGVHD and relapse, their low stem cell content results in slower immune reconstitution and higher risk of graft failure, severe infections and TRM. Recently, results of a Phase I/II trial revealed that single UM171-expanded CB transplant allowed the use of smaller CB units without compromising engraftment. We now report on T cell reconstitution and immune function in patients transplanted with UM171-expanded CB grafts. Methods We performed a retrospective analysis of 20 patients treated with UM171-expanded CB and compared it to a contemporary cohort of 12 patients treated in the same institution who received unmanipulated CB transplant with similar conditioning regimens. Of note, no patient received ATG as part of the conditioning in either cohort. We used flow cytometry and TCR sequencing to evaluate T cell reconstitution, and virus-specific ELISpot assays to evaluate T cell function in the first year post-transplantation. We also categorized infectious events as per definitions of infection severity in the BMT CTN Technical MOP Version 3.0 and report the mean cumulative count of infectious events for each cohort. Results While median T cell dose in graft was at least 2-3x lower for the cohort of patients treated with UM171-expanded CB due to the selection of smaller cords and to cell loss occurring during CD34 selection process, numbers and phenotype of T cells at 3, 6 and 12 months post-transplant were similar in patients treated with UM171-expanded or unmanipulated CB transplant. TCR sequencing analyses revealed that UM171 patients had greater T cell diversity and higher numbers of T cell clonotypes at 12 months post-transplant compared to patients who received unmanipulated CB. Younger UM171 patients (i.e. <40 years old) also showed a more pronounced increase in naïve T cells and recent thymic emigrants (RTE) between 3- and 12-months post-transplant compared to age-matched unmanipulated CB patients, suggesting that UM171-expansion improves thymopoiesis at least in the young patients. This also correlated with the demonstration that UM171 expands common lymphoid progenitors in vitro. ELISpot assays revealed that UM171 patients showed early virus-specific T cell reactivity, at 2- and 3-months post-transplant. Most importantly, UM171 patients had a 2-fold lower frequency of severe (i.e. grade 2-3) infections at 1 year post-transplant, even though time to engraftment of 500 neutrophils was similar between the two cohorts (17 and 20 days for the UM171-expanded and unmanipulated CB cohorts respectively, p=0.94). Conclusion Our data show that the relative T-cell paucity of the UM171 graft is rapidly compensated after transplant with no significant difference observed between the two cohorts in terms of numbers and phenotypes of T cells at 3, 6 or 12 months post-transplant. Although it is difficult to dissect the relative contribution of homeostatic expansion and de novo thymopoiesis, recipients of UM171 grafts had a greater TCR diversity at one year, which was more evident among patients younger than 40 years of age. The prompt immune reconstitution observed in UM171 patients translated into a low rate of severe (grade 2-3) infections and no infection-related mortality. These results support rapid and functional T cell reconstitution following UM171 expanded CB transplantation, which likely contributes to the absence of moderate/severe cGVHD, infection-related mortality and late TRM observed in this cohort. Figure legend: Mean cumulative counts of infectious events in patients transplanted with UM171-expanded (blue) or unmanipulated (red) CB. Mean cumulative counts are shown for all infectious events (A), bacterial (B) and viral (C) infections. Events were categorized by type and severity as per BMT CTN guidelines (Appendix 4A). Infectious events of grade 1-3 are shown in pale colors, while more severe events (grade 2-3) are shown in dark colors. Censored patients (including those who relapsed) are indicated with white circles. Figure 1 Disclosures Dumont-Lagacé: ExCellThera: Current Employment. Busque:Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Sauvageau:ExCellThera: Current equity holder in private company, Other: CEO, Patents & Royalties. Cohen:ExCellThera: Consultancy, Other: principal investigator of an ongoing UM171 clinical trial.

New Developments in Allotransplant Immunology

Hematology ◽  
2003 ◽  
Vol 2003 (1) ◽  
pp. 350-371 ◽  
Author(s):  
A. John Barrett ◽  
Katayoun Rezvani ◽  
Scott Solomon ◽  
Anne M. Dickinson ◽  
Xiao N. Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Cytokine Gene ◽  
Post Transplant ◽  
Cytokine Milieu ◽  
Cytokine Gene Polymorphisms

Abstract After allogeneic stem cell transplantation, the establishment of the donor’s immune system in an antigenically distinct recipient confers a therapeutic graft-versus-malignancy effect, but also causes graft-versus-host disease (GVHD) and protracted immune dysfunction. In the last decade, a molecular-level description of alloimmune interactions and the process of immune recovery leading to tolerance has emerged. Here, new developments in understanding alloresponses, genetic factors that modify them, and strategies to control immune reconstitution are described. In Section I, Dr. John Barrett and colleagues describe the cellular and molecular basis of the alloresponse and the mechanisms underlying the three major outcomes of engraftment, GVHD and the graft-versus-leukemia (GVL) effect. Increasing knowledge of leukemia-restricted antigens suggests ways to separate GVHD and GVL. Recent findings highlight a central role of hematopoietic-derived antigen-presenting cells in the initiation of GVHD and distinct properties of natural killer (NK) cell alloreactivity in engraftment and GVL that are of therapeutic importance. Finally, a detailed map of cellular immune recovery post-transplant is emerging which highlights the importance of post-thymic lymphocytes in determining outcome in the critical first few months following stem cell transplantation. Factors that modify immune reconstitution include immunosuppression, GVHD, the cytokine milieu and poorly-defined homeostatic mechanisms which encourage irregular T cell expansions driven by immunodominant T cell–antigen interactions. In Section II, Prof. Anne Dickinson and colleagues describe genetic polymorphisms outside the human leukocyte antigen (HLA) system that determine the nature of immune reconstitution after allogeneic stem cell transplantation (SCT) and thereby affect transplant outcomethrough GVHD, GVL, and transplant-related mortality. Polymorphisms in cytokine gene promotors and other less characterized genes affect the cytokine milieu of the recipient and the immune reactivity of the donor. Some cytokine gene polymorphisms are significantly associated with transplant outcome. Other non-HLA genes strongly affecting alloresponses code for minor histocompatibility antigens (mHA). Differences between donor and recipient mHA cause GVHD or GVL reactions or graft rejection. Both cytokine gene polymorphisms (CGP) and mHA differences resulting on donor-recipient incompatibilities can be jointly assessed in the skin explant assay as a functional way to select the most suitable donor or the best transplant approach for the recipient. In Section III, Dr. Nelson Chao describes non-pharmaceutical techniques to control immune reconstitution post-transplant. T cells stimulated by host alloantigens can be distinguished from resting T cells by the expression of a variety of activation markers (IL-2 receptor, FAS, CD69, CD71) and by an increased photosensitivity to rhodamine dyes. These differences form the basis for eliminating GVHD-reactive T cells in vitro while conserving GVL and anti-viral immunity. Other attempts to control immune reactions post-transplant include the insertion of suicide genes into the transplanted T cells for effective termination of GVHD reactions, the removal of CD62 ligand expressing cells, and the modulation of T cell reactivity by favoring Th2, Tc2 lymphocyte subset expansion. These technologies could eliminate GVHD while preserving T cell responses to leukemia and reactivating viruses.

scholarly journals Head-to-Head Comparison of Haploidentical HSCT Strategies for Hematologic Malignancies: Phase III Hatcy Study of T-Cell-Depleted HSCT with Adjunctive ATIR101 Versus T-Cell-Replete HSCT with Post‐Transplant Cyclophosphamide

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4464-4464
Author(s):  
Denis Claude Roy ◽  
Bernd-Jan Sanson ◽  
Jonas Hylton ◽  
Andrew Sandler ◽  
Stephan Mielke
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Ex Vivo ◽  
Composite Endpoint ◽  
Hematologic Malignancies ◽  
Phase Iii ◽  
Free Survival ◽  
Post Transplant ◽  
Related Mortality

Rationale: Haploidentical allogeneic hematopoietic stem cell transplantation (haplo HSCT) is increasingly used for the treatment of high-risk hematologic malignancies and overcomes limitations of finding a human leukocyte antigen (HLA)-matched donor in a timely manner. Although the most frequently used approach is a T-cell-replete stem cell source followed by in vivo depletion of alloreacting T cells using post-transplant chemotherapy with cyclophosphamide (PTCy), several other approaches have emerged, providing selected or manipulated donor-derived T cells to a T-cell-depleted or alpha/beta T-cell-CD19-depleted stem cell backbone. Here, we present the approach involving T-cell-depleted haplo HSCT complemented by ATIR101, an adjunctive infusion consisting of ex vivo selectively allodepleted, donor-derived, T-cell-enriched leukocytes. ATIR101 can facilitate early immune protection and provide anti-infectious and anti-leukemic activity while minimizing the risk of acute and chronic graft-versus-host disease (GVHD) without the need for post-transplant immunosuppression. ATIR101 is manufactured through the ex vivo use of TH9402 (a rhodamine derivative) and photodynamic treatment, selectively depleting the donor T cells that were activated by the recipient cells. The safety and efficacy of ATIR101 treatment following T-cell-depleted haplo HSCT have been investigated in Phase I and II studies in patients with hematologic malignancies (Roy DC et al. Br J Haematol 2019; ASH 2016, 2018). This strategy is currently being explored in a large, global, randomized Phase III study against a strategy of T-cell-replete HSCT with PTCy as the most commonly applied approach in haplo HSCT. Trial Overview: A randomized, multicenter, open-label Phase III trial (HATCY; CR‐AIR‐009; NCT02999854) is currently enrolling 250 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) to undergo either T-cell-depleted haplo HSCT with adjunctive ATIR101 treatment or T-cell-replete haplo HSCT with PTCy. Trial Design and Methods: Inclusion and exclusion criteria are listed in Table 1. All patients undergo total body irradiation (TBI) or non-TBI myeloablative conditioning. Patients in the ATIR101 arm receive anti-thymocyte globulin (Sanofi, 2.5 mg/kg once daily for 4 days) prior to HSCT and an ATIR101 infusion at a dose of 2 × 106 viable T cells/kg between 28 and 32 days post HSCT. In this group, no post-HSCT immune suppression is administered. Patients in the PTCy arm receive cyclophosphamide (50 mg/kg) on Day 3 and 4 (or 5) post HSCT, with subsequent use of immune suppression for GVHD prophylaxis based on institutional guidelines. The primary endpoint of the study is GVHD- and relapse-free survival (GRFS), a composite endpoint defined as time from randomization until Grade III/IV acute GVHD, chronic GVHD requiring systemic immunosuppressive treatment, disease relapse, or death, whichever occurs first. GRFS was selected because it encompasses overall post-transplant health status, thereby closely reflecting a successful transplant outcome (Holtan SG, Blood 2015). Key secondary endpoints are overall survival, progression‐free survival, relapse‐related mortality, and transplant‐related mortality. A further objective of the study is to compare the effects of the two treatment strategies on quality of life. Approximately 50 sites are planned globally. The analysis is event driven: an interim analysis is planned at 105 GRFS events and the final analysis at 156 GRFS events. All patients will be followed up for at least 24 months post HSCT. Conclusion: This study will determine whether a strategy with a T-cell-depleted HSCT with adjunctive ex vivo selectively allodepleted, donor-derived, T-cell-enriched leukocytes (ATIR101) results in improved outcomes over a strategy with T-cell-replete HSCT with PTCy in patients undergoing haploidentical transplantation. The use of GRFS as a composite endpoint involving freedom of relapse and severe GVHD will allow a unique health-economic assessment and definition of value-based healthcare. Disclosures Roy: Kiadis Pharma: Other: Travel support; University of Montreal: Patents & Royalties: Author on patent; Hopital Maisonneuve-Rosemont: Patents & Royalties: Author on patent. Sanson:Kiadis Pharma: Employment. Hylton:Kiadis Pharma: Employment. Sandler:Kiadis Pharma: Employment. Mielke:Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; IACH: Other: Travel support; DGHO: Other: Travel support; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; EBMT/EHA: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution); Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; ISCT: Other: Travel support; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau.

Haploidentical Stem Cell Transplantation: High Doses of Alloreactive-T Cell Depleted Donor Lymphocytes Administered Post-Transplant Decrease Infections and Improve Survival without Causing Severe Gvhd.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 512-512 ◽  
Author(s):  
Denis-Claude Roy ◽  
Silvy Lachance ◽  
Thomas Kiss ◽  
Sandra Cohen ◽  
Lambert Busque ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Reconstitution ◽  
Chronic Gvhd ◽  
T Cell Depletion ◽  
Post Transplant

Abstract Abstract 512 Delayed immune reconstitution following intensive T cell depletion of the stem cell graft is the main complication limiting broad utilization of haplo-mismatched donors for stem cell transplantion (SCT). Indeed, it results in frequent and rapidly lethal infectious events. The ability to accelerate immune reconstitution following haplo-SCT would provide a unique opportunity to transplant the large number of patients who cannot find an HLA-matched donor. We present results of our Phase I clinical trial of haploidentical allogeneic SCT followed by an “add-back of donor T cells to accelerate immune reconstitution” (ATIR). This donor lymphocyte infusion (DLI) underwent photodynamic depletion (PD) of host-reactive T cells using dibromorhodamine as photosensitizer (Kiadis Pharma). Nineteen patients (11 M, 8 F) with very high-risk hematologic malignancies (mostly refractory or relapsed acute myeloid leukemia (10) and myelodysplastic syndromes (4), and refractory ALL (1), CLL (2), CML (1) and NHL (1)) entered the trial. Median age at SCT was 54 years (range: 19-62). HLA compatibility was 3/6 in 6 pts, 4/6 in 12 pts and 5/6 (DR mismatch) in 1 pt. Increasing doses of PD-treated donor cells (ATIR: 1×104 to 5.0 ×106 CD3+ cells/kg) were administered on day 34±6 after transplant. In the ATIR, greater than 95% of CD4+CD25+ and CD8+CD25+ T cells as well as anti-host cytotoxic T lymphocyte precursors (CTLp) were depleted from DLIs. All stem cell grafts underwent in vitro immunomagnetic T cell depletion using CD34+ positive cell selection (Miltenyi). The myeloablative regimen consisted of TBI (1200 cGy), thiotepa (5 mg/kg) and fludarabine (200 mg/m2). No GVHD prophylaxis was administered. All patients showed complete donor chimerism and durable hematologic engraftment. Five patients developed grade II GVHD affecting skin (n = 5 pts), liver (2 pts) and gastrointestinal tract (1 pt) at a median of 101 days post-SCT. No patient developed grade III-IV acute GVHD. Chronic GVHD developed in 9 pts, mostly in those receiving higher T cell doses. Treatment of acute and chronic GVHD involved steroids, tacrolimus and mycophenolate mofetil in 3 patients, steroids and tacrolimus in 3 pts, and steroids only in 3 pts. GVHD responded rapidly to treatment since the median duration of total immunosuppressive therapy in each patient was 187 days (range: 61-319 d). All 7 patients in cohorts 1-3, who received 1.3×105 or less CD3+ cells/kg, developed infectious complications (100% of pts), with 5 lethal episodes in these 7 pts. In sharp contrast, only 6 (50%) of the following 12 patients (cohorts 4-7) receiving ATIR with the highest CD3+ cell doses (3.2×105 to 5.0×106 CD3+ cells/kg) developed infections (p <0.05), none resulting in a fatal event (p<0.001). Interestingly, CD3 lymphocytes recovered earlier in the last 2 cohorts (6 and 7) receiving 2-5×106 CD3+ cells/kg than in the first 5 cohorts (7.9×105 or less CD3+ cells/kg) (p<0.01). Eight patients died: 4 of relapsed leukemia (3 AML; 1 ALL) and 4 of infections. Overall treatment related mortality (TRM) is 27% at 2 years post-SCT, with a TRM of 0% in patients receiving the highest CD3+ cell doses (cohorts 4-7). The overall survival is 60% at 2 years (median f-up: 12.1 mo; 95% confidence interval at 2 years: 37-83%). The 12 patients in cohorts 4-7 receiving the higher CD3+ cell doses had an improved survival (82% at 2 yrs) over the 7 patients in cohorts 1-3 administered a lower CD3+ cell dose (14% at 2 yrs) (p<0.05). Our results indicate that the post-transplant infusion of an ATIR-PD treated DLI is feasible, results in accelerated T cell reconstitution, and decreases the incidence and severity of infections without inducing severe GVHD. These results suggest a clinical benefit for patients receiving the highest ATIR doses and form the basis of an international pivotal clinical trial to decrease TRM in patients undergoing haploidentical stem cell transplantation. Disclosures: Roy: Kiadis Pharma: Research Funding. Egeler:Kiadis Pharma: Employment.

IL-15 Administration Increases Graft Versus Leukemia Activity in Recipients of Haploidentical Hematopoietic Stem Cell Transplantation,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4027-4027
Author(s):  
Christopher Sauter ◽  
Chandra Biswas ◽  
Cavan Bailey ◽  
Michelle Panis ◽  
Tulin Budak-Alpdogan ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Immune Reconstitution ◽  
Low Dose ◽  
Nk Cell ◽  
Hematopoietic Stem ◽  
Cell Numbers ◽  
Post Transplant ◽  
Graft Versus Leukemia

Abstract Abstract 4027 The success of haploidentical (HI) hematopoietic stem cell transplantation (HSCT), suggests that graft-versus-leukemia (GVL) effect might have a substantial role in this transplant modality. Rigorous T-cell depletion (TCD) of the graft decreases the occurrence of graft-versus-host disease (GVHD) in HI-HSCT, however this results in immunodeficiency and high disease relapse rate, especially in patients with resistant or residual leukemia. Therefore, enhancing GVL activity of HSCT without increasing GVHD is crucial for improving the outcome of haploidentical transplant. Post-transplant IL-15 administration is shown to enhance immune reconstitution, particularly donor-derived NK and CD8+ T cell populations in murine models. We evaluated the efficacy of IL-15 for enhancing GVL effect in recipients of HI-HSCT. For developing clinically relevant haploidentical transplant models, different hybrid mice with B6 background that share the same haplotype (H2Kb) are used for our murine haploindentical transplant experiments. Lethally irradiated B6D2F1/J (H2Kb/d) mice are transplanted with B6CBAF1/J (H2Kb/k) TCD bone marrow (BM) and T cells at varying doses. Some animals were also given P815 tumor cells on the day of transplant. Administration of IL-15 significantly increased the numbers of CD8+ T and NK cells in the spleen and BM in the T cell depleted model at post-transplant day 28. Infusion of very low dose haploidentical T cells (1×104) with TCD-BM resulted in a conflicting effect on immune reconstitution, i.e. increased T cell numbers, and decreased NK cell population. Post-transplant IL-15 administration also changed this immune reconstitution pattern and significantly increased both T and NK cell numbers in recipients of HI-HSCT. In P815 challenged mice that were transplanted with very low dose T cell added TCD-BM, IL-15 administration significantly increased anti-tumor activity of the graft and improved survival (Figure 1) without increasing GVHD. This effect was observed when IL-15 administration was given at a later time point rather than immediately following transplantation, possibly allowing for more donor cell engraftment and T cell proliferation to take place. IL-15 administration without T cell infusion did not result in any survival improvement. We conclude that in our experimental HI transplant models, IL-15 administration augments anti-tumor effect of the HI-HSCT without increasing GVHD risk, and this effect requires presence of donor derived T cells. Disclosures: No relevant conflicts of interest to declare.

A Phase II Trial of Peri-Transplant Palifermin with Busulfan, Melphalan and Fludarabine Followed by T-Cell Depleted Hematopoietic Stem Cell Transplants in Patients with Advanced Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) Evolved From MDS

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1935-1935 ◽  
Author(s):  
Roni Tamari ◽  
Sheetal Ramnat Sheetal ◽  
Deborah Kuk ◽  
Esperanza B. Papadopoulos ◽  
Ann A. Jakubowski ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase Ii ◽  
Immune Reconstitution ◽  
Phase Ii Trial ◽  
Allogeneic Hsct ◽  
Post Transplant ◽  
T Cell Reconstitution ◽  
Preparative Regimen ◽  
Historical Controls

Abstract Abstract 1935 Introduction: The success of allogeneic HSCT in the treatment of advanced MDS has been limited by high incidence of relapse and transplant-related mortality (TRM). The main complications contributing to TRM are graft-vs-host disease (GvHD) and infections. Although T cell depletion has successfully reduced the incidence of GvHD, slow immune reconstitution and high rate of infections have compromised its full potential. T cell reconstitution after transplant requires a functional thymic epithelium. Transplant conditioning regimens damage the thymus and impair the production de novo of T cells. Keratinocyte growth factor (KGF) has an important role in healing the epithelium after injury. Palifermin, a human recombinant form of KGF, decreases the incidence and duration of mucositis after total body irradiation and has been approved by the FDA for this purpose in autologous and allogeneic HSCT. In murine models, KGF given before allogeneic transplant has a protective effect on the thymus and accelerates T cell reconstitution. The aim of this study was to assess whether administration of palifermin peri-transplant decreases TRM and improves the overall and disease-free survival (OS and DFS). This study was designed to reduce one- year TRM from 30% and 35% to 10% in HLA matched and mismatched arms, respectively. Patients: Between 11/2009–05/2012, 42 patients (advanced MDS: 26 or AML evolved from MDS: 16) enrolled on this trial. At transplant, 23 were in CR1, 3 were in second refractory cytopenia phase, and 16 had limited disease (<5% circulating blasts and <9% marrow blasts). The median age was 57.5 years (1–65), with 22 males and 20 females. Conditioning consisted of busulfan (12 doses over three days of 0.8 mg/kg IV for patients > 4 years old or 1.0 mg/kg IV for patients < 4 years old), melphalan (70 mg/m2 IV × 2 days), fludarabine (25 mg/m2 IV × 5 days), and rabbit ATG pre-transplant (2 doses and 3 doses for HLA matched and mismatched recipients, respectively). Palifermin was given according to the approved dose for mucositis prevention: 60 mcg/kg/day IV for 3 consecutive days before the preparative regimen, and 3 doses post transplant (day 0, +24hours, +48hours). Donors were HLA matched (31; 13 related and 18 unrelated) or unrelated mismatched (11). G-CSF mobilized donor peripheral blood stem cells underwent CD34+ selection and depletion of T cells using CliniMACS immunomagnetic selection columns (Milteny Biotec). Results: All 42 patients engrafted, 1 patient developed secondary graft failure. The cumulative incidence of grade III-IV aGvHD at day +100 and 1 year were 4.8% and 10.5%, respectively. The latter increase was due to late-onset acute GvHD. Only 1 of 33 patients at risk developed moderate chronic GvHD. The 2-year OS and DFS were 77% and 65%, respectively, and similar in the two arms (HLA matched and mismatched). The CI of relapse at 1-year was 12 % (similar in the two arms). The 1-year TRM was 20%; 18.4% in the HLA matched group (accrual met) and 22% in the mismatched arm (accrual ongoing). Causes of death were: infections (N=5; 3 HLA matched, 2 HLA mismatched), regimen related toxicity (N=2, liver VOD) and relapse (N=1). The frequency of infections was similar to historical controls; at 3 months post transplant, 30% of patients developed active CMV, EBV, or adenovirus infections, at 6 months 16.6%, and at 12 months 7.1%. The 6-month CI of CMV viremia in CMV seropositive patients was 75% and the 6-month CI of EBV viremia was 31%. Immune reconstitution as measured by CD4 count was slow, similar to historical controls, with median absolute CD4 count at 3 months of 77 cells/μl and 200 cells/μl by 1 year posttransplant. Other parameters to assess safety of this regimen, namely duration of narcotics use and days on TPN to measure severity of mucositis were similar to historical controls (same preparative regimen without palifermin). Conclusion: In this ongoing phase II trial the addition of peri transplant palifermin to a chemotherapy only myeloablative conditioning regimen in recipients of TCD HSCT for advanced MDS decreased the TRM, although did not meet the primary objective of this study (reduction to 10%). Also, there was no reduction in the incidence of viral infections and no improvement in immune reconstitution. The reduction in TRM resulted from early detection of infection and improved treatment options. Disclosures: Perales: SOBI Biovitrum, pharma company: SOBI Biovitrum, pharma company Other. Goldberg:SOBI Biovitrum: Research Funding.

A comparison of murine T-cell–depleted adult bone marrow and full-term fetal blood cells in hematopoietic engraftment and immune reconstitution

Blood ◽  
2002 ◽  
Vol 99 (1) ◽  
pp. 364-371 ◽  
Author(s):  
Benny J. Chen ◽  
Xiuyu Cui ◽  
Gregory D. Sempowski ◽  
Maria E. Gooding ◽  
Congxiao Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Blood Cells ◽  
Immune Reconstitution ◽  
Full Term ◽  
Fetal Blood ◽  
Adult Bone

Umbilical cord blood has been increasingly used as a source of hematopoietic stem cells. A major area of concern for the use of cord blood transplantation is the delay in myeloid and lymphoid recovery. To directly compare myeloid and lymphoid recovery using an animal model of bone marrow and cord blood as sources of stem cells, hematopoietic engraftment and immune recovery were studied following infusion of T-cell–depleted adult bone marrow or full-term fetal blood cells, as a model of cord blood in a murine allogeneic transplantation model (C57BL/6 [H-2b] → BALB/c [H-2d]). Allogeneic full-term fetal blood has poorer radioprotective capacity but greater long-term engraftment potential on a cell-to-cell basis compared with T-cell–depleted bone marrow. Allogeneic full-term fetal blood recipients had decreased absolute numbers of T, B, and dendritic cells compared with bone marrow recipients. Splenic T cells in allogeneic full-term fetal blood recipients proliferated poorly, were unable to generate cytotoxic effectors against third-party alloantigens in vitro, and failed to generate alloantigen-specific cytotoxic antibodies in vivo. In addition, reconstituting T cells in fetal blood recipients had decreased mouse T-cell receptorδ single-joint excision circles compared with bone marrow recipients. At a per-cell level, B cells from fetal blood recipients did not proliferate as well as those found in bone marrow recipients. These results suggest that full-term fetal blood can engraft allogeneic hosts across the major histocompatibility barrier with slower hematopoietic engraftment and impaired immune reconstitution.

scholarly journals Autologous stem cell transplantation aids autoimmune patients by functional renewal and TCR diversification of regulatory T cells

Blood ◽  
2016 ◽  
Vol 127 (1) ◽  
pp. 91-101 ◽  
Author(s):  
Eveline M. Delemarre ◽  
Theo van den Broek ◽  
Gerdien Mijnheer ◽  
Jenny Meerding ◽  
Ellen J. Wehrens ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Regulatory T Cells ◽  
Stem Cell Transplantation ◽  
Clinical Improvement ◽  
Autologous Stem Cell Transplantation ◽  
T Cell Reconstitution ◽  
Key Points ◽  
Autologous Hsct

Key Points Autologous HSCT induces functional renewal of regulatory T cells as well as a strong Treg TCR diversification in autoimmune patients. Adding regulatory T cells to the graft does not lead to additional clinical improvement but results in delayed donor T-cell reconstitution.

scholarly journals Impact of Different T Cell Depletion Protocols on Immune Reconstitution Following Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Amandine Pradier ◽  
Adrien Petitpas ◽  
Anne-Claire Mamez ◽  
Federica Giannotti ◽  
Sarah Morin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Reconstitution ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
The Impact

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic modality for a variety of hematological malignancies and congenital disorders. One of the major complications of the procedure is graft-versus-host-disease (GVHD) initiated by T cells co-administered with the graft. Removal of donor T cells from the graft is a widely employed and effective strategy to prevent GVHD, although its impact on post-transplant immune reconstitution might significantly affect anti-tumor and anti-infectious responses. Several approaches of T cell depletion (TCD) exist, including in vivo depletion using anti-thymocyte globulin (ATG) and/or post-transplant cyclophosphamide (PTCy) as well as in vitro manipulation of the graft. In this work, we analyzed the impact of different T cell depletion strategies on immune reconstitution after allogeneic HSCT. Methods We retrospectively analysed data from 168 patients transplanted between 2015 and 2019 at Geneva University Hospitals. In our center, several methods for TCD are being used, alone or in combination: 1) In vivo T cell depletion using ATG (ATG-Thymoglobulin 7.5 mg/kg or ATG-Fresenius 25 mg/kg); 2) in vitro partial T cell depletion (pTCD) of the graft obtained through in vitro incubation with alemtuzumab (Campath [Genzyme Corporation, Cambridge, MA]), washed before infusion and administered at day 0, followed on day +1 by an add-back of unmanipulated grafts containing about 100 × 106/kg donor T cells. The procedure is followed by donor lymphocyte infusions at incremental doses starting with 1 × 106 CD3/kg at 3 months to all patients who had received pTCD grafts with RIC in the absence of GVHD; 3) post-transplant cyclophosphamide (PTCy; 50 mg/kg) on days 3 and 4 post-HSCT. Absolute counts of CD3, CD4, CD8, CD19 and NK cells measured by flow cytometry during the first year after allogeneic HSCT were analyzed. Measures obtained from patients with mixed donor chimerism or after therapeutic DLI were excluded from the analysis. Cell numbers during time were compared using mixed-effects linear models depending on the TCD. Multivariable analysis was performed taking into account the impact of clinical factors differing between patients groups (patient's age, donor type and conditioning). Results ATG was administered to 77 (46%) patients, 15 (9%) patients received a pTCD graft and 26 (15%) patients received a combination of both ATG and pTCD graft. 24 (14%) patients were treated with PTCy and 26 (15%) patients received a T replete graft. 60% of patients had a reduced intensity conditioning (RIC). 48 (29%) patients received grafts from a sibling identical donor, 94 (56%) from a matched unrelated donor, 13 (8%) from mismatched unrelated donor and 13 (8%) received haploidentical grafts. TCD protocols had no significant impact on CD3 or CD8 T cell reconstitution during the first year post-HSCT (Figure 1). Conversely, CD4 T cells recovery was affected by the ATG/pTCD combination (coefficient ± SE: -67±28, p=0.019) when compared to the T cell replete group (Figure 1). Analysis of data censored for acute or chronic GVHD requiring treatment or relapse revealed a delay of CD4 T cell reconstitution in the ATG and/or pTCD treated groups on (ATG:-79±27, p=0.004; pTCD:-100±43, p=0.022; ATG/pTCD:-110±33, p&lt;0.001). Interestingly, pTCD alone or in combination with ATG resulted in a better reconstitution of NK cells compared to T replete group (pTCD: 152±45, p&lt;0.001; ATG/pTCD: 94±36, p=0.009; Figure 1). A similar effect of pTCD was also observed for B cells (pTCD: 170±48, p&lt;.001; ATG/pTCD: 127±38, p&lt;.001). The effect of pTCD on NK was confirmed when data were censored for GVHD and relapse (pTCD: 132±60, p=0.028; ATG/pTCD: 106±47, p=0.023) while only ATG/pTCD retained a significant impact on B cells (102±49, p=0.037). The use of PTCy did not affect T, NK or B cell reconstitution when compared to the T cell replete group. Conclusion Our results indicate that all TCD protocols with the only exception of PTCy are associated with a delayed recovery of CD4 T cells whereas pTCD of the graft, alone or in combination with ATG, significantly improves NK and B cell reconstitution. Figure 1 Disclosures No relevant conflicts of interest to declare.

Prediction of T-cell reconstitution by assessment of T-cell receptor excision circle before allogeneic hematopoietic stem cell transplantation in pediatric patients

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 886-893 ◽  
Author(s):  
Xiaohua Chen ◽  
Raymond Barfield ◽  
Ely Benaim ◽  
Wing Leung ◽  
James Knowles ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Hematopoietic Stem ◽  
Thymic Function ◽  
T Cell Reconstitution

Abstract The extent and rapidity with which T cells are regenerated from graft-derived precursor cells directly influences the incidence of infection and the T-cell–based graft-versus-tumor effect. Measurement of T-cell receptor excision circles (TRECs) in peripheral blood is a means of quantifying recent thymic T-cell production and has been used after transplantation in many studies to estimate thymus-dependent T-cell reconstitution. We hypothesized that the quality of thymic function before transplantation affects thymus-dependent T-cell reconstitution after transplantation. We used real-time polymerase chain reaction (PCR) to quantify signal-joint TRECs (sjTRECs) before and after transplantation. T-cell reconstitution was evaluated by T-cell receptor β (TCRβ) CDR3 size spectratyping. We tested 77 healthy sibling donors and 244 samples from 26 pediatric recipients of allogeneic hematopoietic stem cell transplantation (AHSCT). Blood from the healthy donors contained 1200 to 155 000 sjTREC copies/mL blood. Patients who had greater than 1200 copies/mL blood before transplantation showed early recovery of sjTREC numbers and TCRβ repertoire diversity. In contrast, patients who had fewer than 1200 copies/mL blood before transplantation demonstrated significantly slower restoration of thymus-dependent T cells. We conclude that the rate of reconstitution of thymus-dependent T cells is dependent on the competence of thymic function in the recipients before transplantation. Therefore, pretransplantation measurement of sjTREC may provide an important tool for predicting thymus-dependent T-cell reconstitution after transplantation.

scholarly journals Keratinocyte growth factor augments immune reconstitution after autologous hematopoietic progenitor cell transplantation in rhesus macaques.

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 441-449 ◽  
Author(s):  
Ruth Seggewiss ◽  
Karin Loré ◽  
F. Javier Guenaga ◽  
Stefania Pittaluga ◽  
Joseph Mattapallil ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Growth Factor ◽  
Immune Reconstitution ◽  
Progenitor Cell ◽  
Rhesus Macaques ◽  
Keratinocyte Growth Factor ◽  
Hematopoietic Progenitor Cell ◽  
Thymic Epithelial Cells ◽  
T Cell Reconstitution

Opportunistic infections contribute to morbidity and mortality after peripheral blood progenitor cell (PBPC) transplantation and are related to a deficient T-cell compartment. Accelerated T-cell reconstitution may therefore be clinically beneficent. Keratinocyte growth factor (KGF) has been shown to protect thymic epithelial cells in mice. Here, we evaluated immune reconstitution after autologous CD34+ PBPC transplantation in rhesus macaques conditioned with myeloablative total body irradiation in the absence or presence of single pretotal body irradiation or repeated peritransplant KGF administration. All KGF-treated animals exhibited a well-preserved thymic architecture 12 months after graft. In contrast, thymic atrophy was observed in the majority of animals in the control group. The KGF-treated animals showed higher frequencies of naive T cells in lymph nodes after transplantation compared with the control animals. The animals given repeated doses of KGF showed the highest levels of T-cell receptor excision circles (TRECs) and the lowest frequencies of Ki67+ T cells, which suggest increased thymic-dependent reconstitution in these animals. Of note, the humoral response to a T-cell–dependent neo-antigen was significantly higher in the KGF-treated animals compared with the control animals. Thus, our findings suggest that KGF may be a useful adjuvant therapy to augment T-cell reconstitution after human PBPC transplantation.

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