Allogeneic Genetically Modified T Cells (HSV-TK) As Adjunctive Treatment in Haploidentical Hematopoietic Stem-Cell Transplantation (haplo-HSCT) of Adult Patients with High-Risk Hematological Malignancies: A Pair-Matched Analysis from the Acute Leukemia Working Party of EBMT

Abstract Introduction. Current approaches to haplo-HSCT rely either on T-cell depletion to overcome the HLA disparity or on the administration of the lymphotoxic agent cyclophosphamide several days after stem cell infusion, with the goal of selectively depleting activated alloreactive lymphocytes in vivo. In both approaches, haplo-HSCT can be associated with prolonged immunodeficiency post-transplantation. Thus, effective approaches to hastening immune reconstitution following transplantation are needed. Zalmoxis¨ is an Advanced Therapy Medicinal Product based on somatic T-cells genetically modified to express the Herpes Simplex Thymidine Kinase (HSV-TK) suicide gene and a truncated form of the human Low Affinity Nerve Growth Factor Receptor (ΔLNGFR) genes (for identification of transduced cells). The expression of the HSV-TK gene, as a suicide gene allows the selective killing of dividing cells upon administration of the pro-drug ganciclovir (GCV). If GvHD occurs, ganciclovir/valganciclovir can be administered. Here we report the results of a pair-matched analysis which compared the outcome of patients who received HSV-TK cells infusion post haplo-HSCT versus those who did not receive any cellular therapy post-transplant. Patients and Methods. The HSV-TK patients' group included 45 patients who were treated as part of 2 prospective trials with various types of high-risk hematologic malignancies. These patients were compared to patients treated with haplo-HSCT reported to the acute leukemia working party registry of the EBMT. Inclusion criteria for the pair-matched analysis encompassed haplo-HSCT transplants performed in adult patients diagnosed with AML/ALL/sAML in CR or relapse at transplantation. To equate the distribution of baseline characteristics between the HSV-TK and control group and to reduce bias in treatment effect estimation, a pair-matched analysis was performed. This analysis, in which pairs of HSV-TK and control subjects sharing similar baseline characteristics were formed, used the following parameters as pair matching factors: patient age, diagnosis (AML, ALL and sAML), disease status at HSCT (CR1, CR2, CR3 or relapse) and time from diagnosis to HSCT. The planned ratio of HSV-TK patients to control patients was one to four. Efficacy outcome measures of this pair-matched analysis were OS, LFS, NRM and relapse incidence (RI). Cumulative incidence rates of chronic GVHD were also analyzed. Results. Overall, 37 HSV-TK-treated patients matched with 140 controls (71 from PT-Cy cohort and 69 from TCD cohort transplanted between 2005 and 2013). The recommended dose and schedule of HSV-TK cells was 1x107 cells/kg given as IV infusion every 30 days for a maximum of 4 times until a circulating T-cell count higher than 100 per μL. The 1st administration should occur between day 21 to day 49 after HSCT. Baseline characteristics of the HSV-TK treated and the control patient population are summarized in the below table. OS at 1-year was significantly improved in the HSV-TK-group compared with the control group (p=0.01). The survival rates were 49% and 37% for HSV-TK- and control group, respectively. The NRM at 1-year was also improved upon treatment with HSV-TK, with 43% for the control group and 22% for the HSV-TK-group (p=0.014). A difference in favor of the HSV-TK-group could also be observed for the 1-year incidence of chronic GvHD with 25% for the control group vs 9% for the HSV-TK-group (p=0.04). The LFS and the RI were not different between the groups. Interestingly, these differences remained similar whether considering the TCD or the PT-CY subgroups). Together the data suggest that the benefit seen in OS is driven by a reduction in the NRM. A further analysis of NRM data revealed that in the control group 34 of 140 (24%) patients died due to infection and 8 of 140 (6%) succumbed due to GvHD. In the HSV-TK population 4 (11%) patients died because of infection and no patient died due to GvHD. This suggests that the reduction in NRM mortality in the HSV-TK population is caused both by a reduction in death due to infection and due to GvHD. Concerning safety, no death was attributed to HSV-TK cells. Acute GvHD resolved in all cases, and activation of the suicide gene by treatment with GCV has contributed to the control of GvHD. Conclusion. The above pair-matched analyzis confirmed the positive impact and benefit of HSV-TK cells as adjunctive treatment in haplo-HSCT with an acceptable safety pattern. Table. Table. Disclosures Bonini: Molmed SpA: Consultancy; TxCell: Membership on an entity's Board of Directors or advisory committees. Ciceri:MolMed SpA: Consultancy.

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T-Cell Reconstitution after Unrelated Donor HSCT Using Immunotherapy with CD25/71 Allodepleted Donor T Cells: Results of the Randomised Icat Study

Blood ◽

10.1182/blood-2019-124404 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1995-1995

Author(s):

Karl S Peggs ◽

Sarah J Albon ◽

Catherine Irving ◽

Rachel Richardson ◽

Joan Casanovas-Company ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Count ◽

Chronic Gvhd ◽

Control Group ◽

Unrelated Donor ◽

Donor T Cells ◽

The Mean ◽

And Control ◽

To Receive

Karl S Peggs and Sarah J Albon contributed equally to the work and are joint first author Introduction Alemtuzumab reduces the incidence of GVHD after unrelated donor stem cell transplant (MUD SCT) but delays immune reconstitution resulting in high morbidity/mortality from viral infections. Previous studies have suggested that adoptive transfer of allodepleted donor T cells (ADTs) improves immunity after SCT but this has never been tested in a randomised study. We developed a methodology for selective immunomagnetic depletion of alloreactive T-cells upregulating CD25 and CD71 after activation with host dendritic cells (DC) and showed that ADTs retain anti-viral responses with minimal host alloreactivity (Samarasinghe et al Blood 2010). We have now tested whether ADTs can safely be used to improve immune reconstitution after MUD SCT for haematological malignancies in a randomised Phase II multi-centre clinical study; ICAT (NCT01827579). Methods Patients undergoing Alemtuzumab-based peripheral blood SCT from a 9/10 or 10/10 MUD for haematological malignancy were randomised 2:1 to receive either the ATIMP (ADTs) or standard of care. Two weeks prior to SCT, patients randomised to ATIMP underwent a leucapheresis from which DCs were generated. Irradiated patient-derived DCs were then co-cultured with peripheral blood mononuclear cells (PBMC) from an unstimulated leucapheresis/500ml blood draw from the donor to activate alloreactive T cells. Four days later, the co-culture was depleted of CD25+ and CD71+ fractions by immunomagnetic depletion on the CliniMACs, sampled for residual alloreactivity and sterility, and cryopreserved. Patients randomised to the ATIMP were scheduled to receive 3 escalating doses of ADTs (0.1x106/Kg at day 30, 0.3x106/Kg at day 60 and 1x106/Kg at day 90 post-SCT) until either there was >grade 1 aGVHD or they had normal circulating T cells (>700/µL). The primary end-point of the study was circulating CD3+ T cell count at 4 months post-SCT with one-sided 15% significance level. Acute/chronic GVHD were graded using the Seattle/NIH criteria respectively. Results Twenty one patients were treated, 13 on the ATIMP arm and 8 on the control arm. The median age was 53 years and 67% (14) were male. 12 were AML/Myelodysplasia, 5 NHL, 3 CLL/CML and 1 HL. The median follow-up time is 14 months. Five of 13 ATIMP patients received 1 dose of ADTs, 4/13 2 doses and 4/13 all 3 doses. The incidence of acute and chronic GVHD was comparable between the arms. Overall, 7/13 ATIMP patients developed significant (>Grade 2) acute GVHD compared to 4/8 of the control arm (p>0.99). 3/13 patients in the ATIMP arm and 2/8 patients in the control arm developed severe aGVHD (all Grade 3). Three of 13 ATIMP cohort patients developed chronic GVHD (1 mild, 1 moderate, 1 severe), compared to 3/8 (all mild) in the control cohort. At 4 months, the circulating CD3+ T cell count mean was 730/µL (range 10-4080) in the ATIMP group and 212.5/µL (range 10-500) in the control group (1-sided p=0.11). However, the data was not normally distributed (Wilcoxon 1-sided p=0.18). Three ATIMP patients had high CD3+ T cell count at 4 months (>1000/µL). At 6 months, the mean circulating CD3+ T cell count was 833.6/µL (range 20-2690) and 327.5/µL (range 10-860). At month 4, the mean PHA stimulation index in the ATIMP arm was 16.8 (range 0.67- 73.1) vs 3.8 (range 1.1-8.2) in the control group. At 4 and 6 months post-SCT, spectratyping analysis showed no evidence of a difference in Vβ diversity between the 2 arms in both CD4+ and CD8+ cells. The 1-year survival rate in the ATIMP cohort is 92% vs 88% in the control, and 1-year disease free survival rate 67% in the ATIMP cohort vs 70% in the control. Conclusions These data suggest that adoptive transfer of ADTs improves T cell reconstitution in some patients after MUD SCT and that the GVHD rates were similar between ATIMP and control groups. Figure 1: Kinetics of T cell recovery after transplant in ATIMP (blue) and Control (red) patients. Mean +/- SEM shown. Figure 1 Disclosures Peggs: Gilead: Consultancy, Speakers Bureau; Autolus: Membership on an entity's Board of Directors or advisory committees. Ghorashian:UCLB: Patents & Royalties: UCLB; Celgene: Honoraria; novartis: Honoraria. Amrolia:UCLB: Patents & Royalties.

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Dose-Reduced Conditioning Followed by Allogeneic Stem Cell Transplantation in Patients with Myelofibrosis. Results from a Multicenter Prospective Trial of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT).

Blood ◽

10.1182/blood.v110.11.683.683 ◽

2007 ◽

Vol 110 (11) ◽

pp. 683-683 ◽

Cited By ~ 5

Author(s):

Nicolaus Kroeger ◽

Ernst Holler ◽

Guido Kobbe ◽

Martin Bornhaeuser ◽

Rainer Schwerdtfeger ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Chronic Gvhd ◽

Prospective Trial ◽

Conditioning Regimen ◽

Working Party ◽

Unrelated Donor ◽

Jak2 Mutation ◽

Cytogenetic Abnormalities ◽

Excellent Outcome

Abstract The major limitation of allogeneic stem cell transplantatiopn (SCT) in patients (pts) with myelofibrosis is the high treatment related mortality. We performed a prospective multicenter trial of a dose-reduced conditioning regimen, consisting of busulfan (10 mg/kg orally or 8mg/kg i.v), fludarabine (180 mg/m2) and anti-thymocyte globulin (ATG Fresenius: 30–60 mg/kg) followed by allogeneic SCT in pts with myelofibrosis. From 2002 to 2006, 104 pts with a median age of 55 years (range: 32–68) andlow risk with constitutional symptoms (18%) or intermediate risk (n= 58%) and high risk (n=19%) were included. Cytogenetic abnormalities and JAK2 mutation were noted in 22% and 48%, respectively. Bone marrow histology showed advanced fibrosis (MF 2 and 3) in all pts. All but 3 pts received peripheral blood stem cells as graft source either from related (n=33) or unrelated donor (n=71). All but one (1%) pts showed leukocyte and platelet engraftment after a median of 18 and 21 days, respectively. The median duration of leukocyte aplasia was 9 days (range: 3–21). Acute GvHD grade II to IV occurred in 19% and severe aGvHD III/IV in 7%, while chronic GvHD was seen in 32% of the pts. Non-relapse mortality at 1 year was 19% (95% CI: 11–27%) and significantly lower for pts younger than 50 years of age (0% vs 27%, p=0.004) and for pts with low risk vs intermediate/high risk disease (0% vs 27%, p= 0.02). The cumulative incidence of relapse at 3 years was 29% (95%CI: 15–43%). The 3 year overall (OS) and event-free survival (EFS) was 70% (95% CI 60–80%) and 55% (95% CI 42–68%). Significant factors for improved 3 year OS and EFS were age less than 50 years (92% vs 62%, p=0.003 and 79% vs 46%, p= 0,004) and low vs intermediate/high risk (100% vs 62%, p=0.01 and 72% vs 48%, p= 0.02), while no impact on survival was seen for cytogenetic abnormalities, JAK2 mutation status and donor (related vs unrelated). These prospective multicenter study show excellent outcome of an busulafan/fludarabine based reduced conditioning regimen followed by allogeneic SCT in pts with myelofibrosis.

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Partial T-Cell Depletion By Low-Dose Anti-Thymocyte Globulin to Reduce Severe Acute and Chronic Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation

Blood ◽

10.1182/blood.v126.23.5470.5470 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5470-5470

Author(s):

Osamu Imataki ◽

Yumiko Ohbayashi ◽

Yukiko Ohue ◽

Harumi Matsuka ◽

Makiko Uemura ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

Low Dose ◽

Chronic Gvhd ◽

Cell Depletion ◽

Control Group ◽

T Cell Depletion ◽

Stem Cell Source ◽

Gvhd Prophylaxis

Abstract Background: T cells from a stem cell source are inevitably contaminated, and over 5.0×104/kg T cells are thought to induce graft-versus-host disease (GVHD) in HLA-mismatched or haplo-identical stem cell transplantations (SCTs) [4]. To suppress GVHD reactions, a procedure for T-cell depletion (TCD) was developed over the past several decades, especially for HLA-mismatched and haplo-identical SCTs, which are at high risk for GVHD. To reduce the incidence of GVHD, a potentially effective agent is anti-thymocyte globulin (ATG), which is generally administered at a dose of ≥ 5-10 mg/kg. Based on data regarding the use of ATG for the treatment of aplastic anemia, we hypothesized that ATG might accommodate engraftment and inhibit GVHD. We attempted to use a lower dose of ATG to decrease non-relapse mortality (NRM) in Japanese patients undergoing an HLA-matched SCT. Patients and method: We treated patients with hematological diseases who underwent an allogeneic SCT after March 2010 without or with 2.5 mg/kg ATG. The inclusion criteria for underlying disease included both hematological malignancies and bone marrow failures. All consecutive patients transplanted from an allogeneic related or unrelated donor were included. Cord blood transplantations were omitted from this analysis. The patients who underwent an SCT before February 2010 (n=20) were examined as the control group without ATG treatment. ATG was administered 1 day prior to the transplantation day at 2.5 mg/kg with 500 mg/body methylpredonisolone as a preconditioning procedure. GVHD prophylaxis, tacrolimus 0.03 mg/kg and short-term MTX (10-7-7 mg/m2) was adapted for both the ATG group and the control group. Results: Thirty-nine (21 male, 18 female) recipients were recruited (median age 49 yrs, range 19-64 yrs). Their underlying diseases were acute myeloid leukemia (n=14), acute lymphoblastic leukemia (n=10), myelodysplastic syndrome (n=5), lymphoma (n=7), and myeloma, aplastic anemia, and other malignancy (n=1 each). Preparation regimens were myeloablative for 17 patients (14 cyclophosphamide [CY]/total body irradiation [TBI], two busulfan [BU]/CY, and another) and non-myeloablative for the other 22 patients (14 fludarabine/melphalan [Flu/Mel] and eight Flu/BU). All but one patient achieved engraftment, and one secondary graft failure was observed. The overall incidences of acute and chronic GVHD were 63.2% and 15.8% for the ATG-treated patients (40.0% and 25.0% for the control cohort), respectively. Acute GVHD (grades II to IV and III to IV) in the recipients who received ATG occurred in 21.1% and 0.0% (control cohort, 10.0% and 5.0%), respectively. The estimated probability of overall survival (OS) 2.5 yrs after transplantation was 77.8% for the ATG group (controls, 57.1%). The relapse rate 2.5 yrs after transplantation was 21.1% and 20.0% in the ATG and control groups, respectively. The NRM rate was decreased after ATG treatment: 25.0% vs. 10.5% (not significant). The causes of mortality with or without ATG were recurrent diseases (n=1 and 2), infection (n=1 and 0), and adverse events caused by transplant-related complication (n=1 and 5), respectively. No deaths due to acute or chronic GVHD occurred. Discussion: Low-dose ATG could suppress the incidence of severe acute GVHD and chronic GVHD without increasing the NRM, although our study design did not have enough power to make a conclusion about the efficacy of low-dose ATG. However, partial T-cell depletion may be effective for HLA-matched SCT recipients. Our results show that ATG at 2.5 mg/kg can be used safely for the Japanese transplant population of HLA-matched donors. Low-dose ATG is a potential treatment to partially disempower T cells from a stem cell source, which are inevitably contaminated. Recent developments in the prophylaxis for GVHD, such as selective cytotoxic T-cell depletion by using a post-transplant CY regimen, are promising strategies to fully suppress T cells as the GVHD enhancer. Previous studies revealed the clinical efficacy of GVHD prophylaxis but did not clarify the significance of its survival benefit. Likewise, our present findings indicated a lack of survival benefit by ATG treatment in this small study. However, the low-dose ATG contributed to a reduction of severe GVHD. Although early mortality after transplantation is decreasing, late-onset comorbidity including chronic GVHD remains a significant problem. Disclosures No relevant conflicts of interest to declare.

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Excellent Outcomes of Combined Haploidentical and Cord-Blood (Haplo-Cord) Transplantation and HLA-Matched Sibling (Matched-Sib) Donor Transplantation for High-Risk Patients with Severe Aplastic Anemia (SAA) Refractory to Immunosuppressive Therapy

Blood ◽

10.1182/blood.v128.22.4689.4689 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4689-4689 ◽

Cited By ~ 1

Author(s):

Enkhtsetseg Purev ◽

Georg Aue ◽

Phuong Vo ◽

Ritesh Kotecha ◽

Jennifer S. Wilder ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

High Risk ◽

Cord Blood ◽

Immunosuppressive Therapy ◽

Graft Failure ◽

Chronic Gvhd ◽

Neutrophil Recovery ◽

Cd34 Cells ◽

Matched Sibling

Abstract Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for SAA unresponsive to immunosuppressive therapy (IST). For SAA patients (pts) with a HLA-identical sibling donor, the use of peripheral-blood (PB) grafts have been reported to have increased risk of graft-versus-host disease (GVHD) compared with using the bone marrow (BM) as the stem cell source. For pts lacking an HLA-identical donor, transplantation using unrelated cord blood (UCB) or haplo-identical donors has historically been associated with high graft failure rates and poor survival. Here we report and compare the clinical outcomes for two novel transplantation strategies under investigation at our center aimed at improving engraftment and survival and reducing GVHD in high-risk SAA pts refractory to IST: combined haploidentical and cord-blood (haplo-cord) transplants vs. HLA-matched sibling (matched-sib) donor PB HSCT with partial T-cell depletion. Methods: Forty-seven pts with SAA or SAA evolved to MDS that was unresponsive to IST underwent HSCT at a single center between 2008 and 2016, and received either a haplo-cord transplant (n= 28; pt eligibility included lack a HLA-matched donor but availability of a haploidentical relative, a ≥4/6 HLA matched UCB unit and severe neutropenia with an ANC<500 cells/µL) or an HLA matched-sib transplant (n=19). Both cohorts were treated with cyclophosphamide, ATG, and fludarabine, with the haplo-cord cohort also receiving 200 cGy of total body irradiation. For the haplo-cord cohort, pts received a CD34-selected G-CSF mobilized haplo-donor allograft combined with a ≥ 4/6 HLA-matched UCB unit (minimum TNC dose ≥1.5x107 cells/kg). For the matched-sib cohort, pts received G-CSF-mobilized PBSC-allograft containing high numbers of CD34+ selected cells combined with BM transplant equivalent-dose of non-mobilized CD3+T-cells/kg from a ≥9/10 HLA-matched sibling donor. GVHD prophylaxis included tacrolimus and MMF (haplo-cord) or CSA and MTX (matched-sib). Results: The median age at transplant was 20 years (range 5-49) in haplo-cord and 22 years (6-67) in matched-sib. Pts were heavily transfused and allo-immunized: pre-transplant serum ferritin was markedly elevated at a median 3368 µg/l (range 980-21465) and 1978 µg/l (161-13928) for haplo-cord and matched-sib cohorts, respectively. For the haplo-cord cohort, 18 pts received a 4/6 and 10 pts received a ≥5/6 HLA-matched UCB unit; UCB units contained a median of 3.6x107 TNCs/kg and 1.5x105 CD34+ cells/kg; haplo-grafts contained a median of 3.2x106 CD34+ cells/kg and 1.0x103 CD3+ T-cells/kg. For the matched-sib cohort, PBSC allografts from 10/10 (n=18) or 9/10 (n=1) HLA-matched donors contained a median of 8x106CD34+ cells/kg and 2x107 non-mobilized CD3 T-cells/kg. At a median follow-up of 40 months in haplo-cord and 32 months in matched-sib, most post-transplant clinical outcomes were comparable between two cohorts. In both cohorts, all pts (100%) had donor engraftment with neutrophil recovery occurring at a median of 10 days (range 6-28) in haplo-cord and 14 days (10-23) in matched-sib (Figure); median times to platelet recovery were 28 and 18 days. No patients in the matched-sib and only one pt (4%) in haplo-cord group developed late graft failure. The 200-day survival were 100% and 95%, and overall survival at 5 years were 91% and 87% in haplo-cord and matched-sib cohorts, respectively (Figure, P=0.7). The cumulative incidences of grade II-IV and III-IV acute GVHD were 37% and 4% in haplo-cord, compared to 21% and 11% in matched-sib. The cumulative incidence of chronic GVHD was higher in haplo-cord than matched-sib (45% vs.12%), however, only 8% and 0% extensive chronic GVHD occurred in two cohorts, respectively. Conclusion: Both transplant regimens being studied our center for SAA pts with high-risk ATG-refractory disease resulted in rapid neutrophil recovery, durable donor engraftment and excellent long-term survival. Despite pts being heavily transfused, iron overloaded and HLA allo-immunized, adverse outcomes of graft failure, severe acute grade III-IV GVHD and extensive chronic GVHD rarely occurred with either transplant approach. Remarkably, most transplant outcomes including survival were similar between haplo-cord and matched-sib cohorts, establishing haplo-cord transplantation to be a viable and promising transplant strategy for SAA pts who lack an HLA identical sibling. Figure Figure. Disclosures Young: GSK/Novartis: Research Funding.

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Anti-GD2 Based Immunotherapy Prevents Late Events in High-Risk Neuroblastoma Patients over 18 Months at Diagnosis

Cancers ◽

10.3390/cancers13194941 ◽

2021 ◽

Vol 13 (19) ◽

pp. 4941

Author(s):

Michelle Tas ◽

Lisa Dootjes ◽

Marta Fiocco ◽

Ronald de Krijger ◽

Miranda Dierselhuis ◽

...

Keyword(s):

High Risk ◽

Maintenance Therapy ◽

Single Agent ◽

Control Group ◽

Free Survival ◽

Gm Csf ◽

Landmark Point ◽

Baseline Characteristics ◽

And Control

Background: Anti-GD2 based immunotherapy has improved overall (OS) and event free survival (EFS) for high-risk neuroblastoma (HR-NBL) patients. Here, we evaluate the long-term efficacy of anti-GD2 immunotherapy in combination with isotretinoin, GM-CSF, and IL-2. Methods: Dutch HR-NBL patients treated with immunotherapy according to the COG-ANBL0032 protocol (n = 47) were included and compared to historical controls (n = 37) treated with single-agent isotretinoin maintenance therapy. Survival time was calculated from start of the maintenance therapy. Results: The study and control group were similar concerning baseline characteristics. In the complete cohort, 5 year OS was 64±7% and 49±8% for the immunotherapy group and the control group, respectively (p = 0.16). Five year EFS was 57±7% and 41±8%, respectively (p = 0.16). In the subgroup of patients ≥ 18 months, 5-yr OS was 63±8% and 39±9, respectively (p = 0.04) and EFS 54±8% and 29±8%, respectively (p = 0.05). Landmark analysis for EFS with landmark point at 6 months after start of maintenance suggests a larger effect on the prevention of late than early events. Conclusions: This study is the first to confirm the results of the COG-ANBL0032 study in a cohort treated with a different induction regimen. Anti-GD2 immunotherapy prevents late events, most significantly in patients older than 18 months of age at diagnosis.

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Selective Allodepletion by TH9402-Mediated Photosensitization Results in Early Full Donor T Cell Reconstitution in the Absence of High-Grade, Acute GvHD and Is Associated with Favorable Outcome after HLA Matched Sibling SCT for Hematologic Malignancies

Blood ◽

10.1182/blood.v112.11.1168.1168 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1168-1168

Author(s):

Stephan Mielke ◽

Aarthi Shenoy ◽

Vicki S. Fellowes ◽

Katayoun Rezvani ◽

Bipin N. Savani ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

High Risk ◽

Ex Vivo ◽

Chronic Gvhd ◽

Hematologic Malignancies ◽

Infectious Complications ◽

High Risk Population ◽

Donor T Cells

Abstract Selective allodepletion (SD) is a strategy to eliminate host-reactive donor T-cells from allografts to prevent graft versus host disease (GvHD) while conserving useful donor immunity. We developed a semi-closed, GMP-quality, clinical scale SD process where donor-derived lymphocytes are stimulated with patient-derived T-cell antigen presenting cells in an ex vivo mixed lymphocyte reaction (MLR). Alloactivated donor T cells preferentially retain the photosensitizer 4,5-dibromorhodamine 123 (TH9402), rendering them susceptible to elimination by exposure to visible light in a photodepletion device (Kiadis Pharma Inc, The Netherlands). After Food and Drug Administration and Institutional Review Board approval we initiated a clinical trial where HLA-identical sibling recipients with hematological (non T-cell) malignancies received a CD34-cell selected transplant (Miltenyi, Germany) containing less then 1 × 104 T cells/kg together with 5 × 106/kg viable SD donor T cells on day 0, using an age-adapted, radiation-based preparative regimen (FluCyTBI). Low-dose cyclosporine was used as sole immunosuppression in the absence of GvHD. Eleven patients (median age 43 (28–68) years with ALL, MDS, CML, mantle cell lymphoma (MCL), or AML) were transplanted with a median follow-up of 240 (43–400) days. Nine patients were considered high risk. Patients received a stem cell product containing a median of 6.0 (3.9–9.5) ×106/kg CD34+ stem cells in addition to 5×106/kg SD T cells. Absolute lymphocyte recovery was rapid (median 834 (384–2486) cells/μL day 30 post transplant) [Fig A]. Early T cell chimerism was donor-dominated (median 66% (6–95) on day 14, and 97% (82–100) on day 30, and 100% (92–100) on day 45 [Fig B]. One patient received an unmanipulated DLI to treat a delayed fall in T cell chimerism. Three patients developed steroid-sensitive grade II aGvHD of skin (N=2) and gut (N=1) but no grade III–IV aGvHD occurred after transfusion of the photodepleted lymphocytes [Fig C]. Two patients developed limited chronic GvHD. Only one patient, transplanted for refractory MCL, relapsed 340 days after transplant. One patient died of infectious complications and GvHD 330 days after transplant after receiving an unmanipulated DLI in her home country for suspected, but subsequently unconfirmed relapse. Eight patients reactivated CMV but were successfully treated. These results demonstrate for the first time clinical feasibility of photodepletion-based SD stem cell allotransplants in matched siblings. Robust lymphocyte recovery and early donor chimerism with a low relapse incidence in a high-risk population suggest functionality of SD T cells in the absence of severe GvHD, which should allow further reduction of immunosuppression to optimize disease control in future studies.

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CD3/CD19 Depleted Grafts for Haploidentical Stem Cell Transplantation in Children: Results of a Pilot Study.

Blood ◽

10.1182/blood.v108.11.3121.3121 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3121-3121

Author(s):

Peter J. Lang ◽

Ingo Mueller ◽

Johann Greill ◽

Peter Bader ◽

Michael Schumm ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

High Risk ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Control Group ◽

Study Group ◽

Preliminary Results ◽

Conditioning Regimens ◽

Active Disease

Abstract Profound depletion of T and B cells is a fundamental prerequisite for haploidentical transplantation. We present our preliminary results with a direct depletion procedure using antiCD3/antiCD19 coated magnetic microbeads and the CliniMACS™ device. Only patients with high risk malignancies (n=25, most of them had active disease or relapsed after previous trp.) or with nonmalignant diseases and high risk of graft failure (n=2) were included. The diagnoses were: AML/MDS/CML (n=13), ALL(n=6), relapsed Neuroblastoma/Ewing-/Rhabdomyosarcoma (n=6), SAA, PNH (n=2); Remission status: NR=8, 2nd transplantation=10, CR/CP1=3, CR2–4=6. The patients received either TBI or Bu based standard conditioning regimens (n=9) or a toxicity reduced protocol (Flud, TT, Mel, OKT3, MMF, n=18). The grafts comprised a median number of 16x106/kg (7–41) stem cells as well as high amounts of NK-cells (137x106 (9–550)) and monocytes/granulocytes (6x108 (0.6–13)) with 49x103/kg (7–200) residual CD3+ cells and <0.01% CD20+ cells. Primary engraftment occurred in 89% of patients (after reconditioning and second stem cell donation:100%). Median time to reach >500 neutrophiles/μl and independence from platelet substitution was 10 and 9 days respectively. Recovery of CD3+ cells was favorable (d90: 320/-l, d180: 600/μl). Acute GvHD grade 0–1 occurred in 74%, 26% had GvHD grade II. Limited chronic GvHD occurred in 4 patients. No transplant related mortality (TRM) and, in particular, no lethal infections were observed. 13/27 patients (49%) were alive with a median follow up of 0.8 years (3 months – 2.1 years). Single cause of death was relapse. Disease status was predictive: 8/9 patients with leukemias and active disease relapsed, whereas only 2/10 patients in CR relapsed. 2/6 patients with solid tumors are alive. Recovery of platelets was faster in patients with CD3/CD19 depleted grafts than in a historical control group of patients (n=53) transplanted with haploidentical positive CD34+ selected standard grafts (23 vs. 9 days, p<0.01). No lethal viral infections occurred in the study group due to the fast T cell recovery, whereas in patients with positive selected grafts a cumulative incidence of 18% was observed. The toxicity-reduced conditioning regimen helped to avoid any other TRM, despite intensive pretreatment (including previous transplantation) of the patients. Conclusions: our preliminary results indicate that CD3/CD19 selected grafts can improve immunoreconstitution and TRM. Engraftment rates similar to that of patients with myeloablative standard conditioning regimens and positive selected stem cells could be achieved, although most patients of the study group received an intensity reduced regimen. However, the outcome was poor in patients with active disease. Thus, further options have to be investigated to increase the potential antileukemic activity of donor derived effector cells.

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Randomized phase III trial of haploidentical HCT with or without an add back strategy of HSV-TK donor lymphocytes in patients with high-risk acute leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.6541 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 6541-6541

Author(s):

Claudio Bordignon ◽

Chiara Bonini ◽

Barbara Sarina ◽

Antonio Lambiase ◽

Fabio Ciceri

Keyword(s):

Stem Cell ◽

High Risk ◽

Immune Reconstitution ◽

Chronic Gvhd ◽

Suicide Gene ◽

Phase Iii ◽

Unrelated Donor ◽

Cell Transplant ◽

Phase Iii Trial ◽

Donor Lymphocytes

6541 Background: Suicide gene therapy applied to allogeneic stem cell transplantation has been tested in several trials. When exposed to ganciclovir, donor lymphocytes expressing herpes simplex thymidine kinase suicide gene (TK cells) are selectively eliminated. In a phase I-II trial (Ciceri, Bonini, Lancet Oncology 2009,489-500), TK cells were infused in patients after haploidentical transplantation. Of 50 patients enrolled, 28 received transduced-TK cells and 22 achieved rapid immune reconstitution, with a non-relapse mortality of 14%. GvHD after DLI-TK infusion was reported in 30% of patients and in all cases was fully controlled by ganciclovir treatment. Methods: High risk leukemia patients in first or subsequent complete remission are currently randomized in a 2-arm (3:1 ratio) phase III trial with or without the add-back strategy of HSV-TK donor lymphocytes in patients underwent T-depleted haploidentical stem cell transplant. Primary end point is disease-free survival (DFS), while secondary end points included overall survival, non-relapse mortality, immune reconstitution, acute and chronic GvHD incidence, and relapse incidence. For the primary analysis of DFS 170 patients (127 patients in the experimental group and 43 patients in the control) are required to detect an hazard ratio of 0.55 with at least 80% power for 2-sided 0.05 level test. Patients are eligible for the study if they are older than 18 years-old, absence of timely and suitable HLA matched family or unrelated donor, and have a ECOG performance status < 2. Patients are stratified by state of disease, ECOG PS and country before randomization. Results: Transduced lymphocytes are given to patients between day +21 and day +49 after haploidentical HCT in the absence of spontaneous immune reconstitution and/or development of GvHD. In absence of immune reconstitution and GvHD after the first TK-cells add-back further 3 infusions could be administered 30 days after the last infusion. TK lymphocytes dose is 1 x10^7 CD3/Kg. Conclusions: The study (TK008) is currently open to accrual in EU, US, Israel (clinicaltrials.gov:00914628).

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THE RISK FACTORS OF MOLAR PREGNANCY

Journal of Medicine and Pharmacy ◽

10.34071/jmp.2017.1.8 ◽

2017 ◽

pp. 53-58

Author(s):

Lam Huong Le

Keyword(s):

High Risk ◽

Gestational Trophoblastic Disease ◽

Living Standard ◽

Control Group ◽

Uterine Perforation ◽

Molar Pregnancy ◽

Health It ◽

Pregnancy Risk ◽

History Of ◽

And Control

Objectives: Molar pregnancy is the gestational trophoblastic disease and impact on the women’s health. It has several complications such as toxicity, infection, bleeding. Molar pregnancy also has high risk of choriocarcinoma which can be dead. Aim: To assess the risks of molar pregnancy. Materials and Methods: The case control study included 76 molar pregnancies and 228 pregnancies in control group at Hue Central Hospital. Results: The average age was 32.7 ± 6.7, the miximum age was 17 years old and the maximum was 46 years old. The history of abortion, miscarriage in molar group and control group acounted for 10.5% and 3.9% respectively, with the risk was higher 2.8 times; 95% CI = 1.1-7.7 (p<0.05). The history of molar pregnancy in molar pregnancy group was 9.2% and the molar pregnancy risk was 11.4 times higher than control group (95% CI = 2.3-56.4). The women having ≥ 4 times births accounted for 7.9% in molar group and 2.2% in control group, with the risk was higher 3.8 times, 95% CI= 1.1-12.9 (p<0.05). The molar risk of women < 20 and >40 years old in molar groups had 2.4 times higher than (95% CI = 1.1 to 5.2)h than control group. Low living standard was 7.9% in molar group and 1.3% in the control group with OR= 6.2; 95% CI= 1.5-25.6. Curettage twice accounted for 87.5%, there were 16 case need to curettage three times. There was no case of uterine perforation and infection after curettage. Conclusion: The high risk molar pregnancy women need a better management. Pregnant women should be antenatal cared regularly to dectect early molar pregnancy. It is nessecery to monitor and avoid the dangerous complications occuring during the pregnancy. Key words: Molar pregnancy, pregnancy women

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Early Use of Corticosteroid May Prolong SARS-CoV-2 Shedding in Non-Intensive Care Unit Patients with COVID-19 Pneumonia: A Multicenter, Single-Blind, Randomized Control Trial

Respiration ◽

10.1159/000512063 ◽

2021 ◽

pp. 1-11

Author(s):

Xiao Tang ◽

Ying-Mei Feng ◽

Ji-Xiang Ni ◽

Jia-Ying Zhang ◽

Li-Min Liu ◽

...

Keyword(s):

T Cells ◽

Randomized Control Trial ◽

Corticosteroid Treatment ◽

Clinical Deterioration ◽

Control Group ◽

Number Of Patients ◽

Early Use ◽

Randomized Control ◽

And Control ◽

Single Blind

Background: There is still no clinical evidence available to support or to oppose corticosteroid treatment for coronavirus disease 2019 (COVID-19) pneumonia. Objective: To investigate the efficacy and safety of corticosteroid given to the hospitalized patients with COVID-19 pneumonia. Methods: This was a prospective, multicenter, single-blind, randomized control trial. Adult patients with COVID-19 pneumonia who were admitted to the general ward were randomly assigned to either receive methylprednisolone or not for 7 days. The primary end point was the incidence of clinical deterioration 14 days after randomization. Results: We terminated this trial early because the number of patients with COVID-19 pneumonia in all the centers decreased in late March. Finally, a total of 86 COVID-19 patients underwent randomization. There was no difference of the incidence of clinical deterioration between the methylprednisolone group and control group (4.8 vs. 4.8%, p = 1.000). The duration of throat viral RNA detectability in the methylprednisolone group was 11 days (interquartile range, 6–16 days), which was significantly longer than that in the control group (8 days [2–12 days], p = 0.030). There were no significant differences between the 2 groups in other secondary outcomes. Mass cytometry discovered CD3+ T cells, CD8+ T cells, and NK cells in the methylprednisolone group which were significantly lower than those in the control group after randomization (p < 0.05). Conclusions: From this prematurely closed trial, we found that the short-term early use of corticosteroid could suppress the immune cells, which may prolong severe acute respiratory syndrome coronavirus 2 shedding in patients with COVID-19 pneumonia. Trial Registration: ClinicalTrials.gov, NCT04273321.

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