Cell Depletion Therapy for Blood Cancers
Recruiting in Palo Alto (17 mi)
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Medical College of Wisconsin
Must not be taking: Chemotherapy, Radiation, Immunotherapy, others
Disqualifiers: Pregnancy, Active malignancy, others
No Placebo Group
Approved in 3 Jurisdictions
Trial Summary
What is the purpose of this trial?This is a single arm pilot study for patients with hematologic malignancies receiving unrelated or haploidentical related mobilized peripheral stem cells (PSCs) using the CliniMACS system for alpha/beta T cell depletion plus CD19+ B cell depletion with individualized ALC-based dosing of ATG to study impact on engraftment, GVHD, and disease free survival
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications. However, you cannot be receiving other chemotherapy, radiation, or immunotherapy treatments for your disease while participating in this trial.
What data supports the effectiveness of the treatment MCW Alpha/Beta T-Cell and B-Cell Depletion With Targeted ATG Dosing for blood cancers?
Research shows that using anti-thymocyte globulin (ATG) in treatments can reduce the risk of graft-versus-host disease (a condition where transplanted cells attack the body) and improve survival rates in patients undergoing stem cell transplants for blood cancers. ATG has also demonstrated antitumor effects, including inducing cell death in various blood cancer cells.
12345Is cell depletion therapy using anti-thymocyte globulin (ATG) safe for humans?
Anti-thymocyte globulin (ATG) is generally considered safe for humans, but it can have side effects. Studies show it can reduce the risk of graft-versus-host disease (a condition where transplanted cells attack the body) but may increase the risk of infections like cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Some patients experienced severe infections and gastrointestinal issues, but overall survival rates were high in trials.
16789How is the drug MCW Alpha/Beta T-Cell and B-Cell Depletion With Targeted ATG Dosing different from other treatments for blood cancers?
This drug is unique because it uses anti-thymocyte globulin (ATG) to deplete specific immune cells, potentially reducing complications like graft-versus-host disease (a condition where transplanted cells attack the body) while maintaining antitumor effects, which is not commonly seen with other treatments.
1231011Eligibility Criteria
This trial is for patients under 25 with various blood cancers like leukemia and lymphoma, who are in remission or have minimal residual disease. They must be generally healthy, not pregnant, agree to use contraception, and can't be on other cancer treatments or part of another early-phase clinical study.Inclusion Criteria
My leukemia shows no minimal residual disease.
My donor's genetic markers have been closely matched to mine.
My lymphoma is currently in remission after a relapse.
+21 more
Exclusion Criteria
No suitable donor
Participating in a concomitant Phase 1 or 2 study involving treatment of disease
Pregnant or lactating patients are ineligible
+3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive alpha/beta T cell and B cell depleted allogeneic transplantation with individualized dosing of ATG
4-6 weeks
Follow-up
Participants are monitored for engraftment, GVHD, and disease-free survival
12 months
Participant Groups
The study tests a cell sorting technique (CliniMACS) for young patients receiving stem cells from donors. It aims to remove certain immune cells to see if it helps with transplant success, reduces graft-versus-host disease (GVHD), and improves survival without the disease coming back.
1Treatment groups
Experimental Treatment
Group I: Alpha/Beta T cell depletion (TCD) plus CD19+ depletionExperimental Treatment1 Intervention
Alpha beta T cell and B cell depleted allogeneic transplantation with individualized dosing of ATG for patients with hematologic malignancies
MCW Alpha/Beta T-Cell and B-Cell Depletion With Targeted ATG Dosing is already approved in United States, United States, European Union for the following indications:
๐บ๐ธ Approved in United States as Thymoglobulin for:
- Acquired aplastic anemia
- Renal allograft rejection
- Prevention of graft-versus-host disease
๐บ๐ธ Approved in United States as Atgam for:
- Acquired aplastic anemia
- Renal allograft rejection
๐ช๐บ Approved in European Union as Grafalon for:
- Acquired aplastic anemia
- Renal allograft rejection
- Prevention of graft-versus-host disease
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Children's WisconsinMilwaukee, WI
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Who Is Running the Clinical Trial?
Medical College of WisconsinLead Sponsor
References
Myeloablative intensified conditioning regimen with in vivo T-cell depletion (ATG) followed by allografting in patients with advanced multiple myeloma. A phase I/II study of the German Study-group Multiple Myeloma (DSMM). [2013]We investigated toxicity and efficacy of in vivo T-cell depletion with anti-thymocyte globulin (ATG) as part of an intensified myeloablative conditioning regimen followed by allogeneic stem cell transplantation in patients with advanced multiple myeloma. The conditioning regimen consisted of modified total body irradiation, busulfan and cyclophosphamide (n=15) or in the case of prior dose-limiting radiotherapy of busulfan and cyclophosphamide (n=3). The median age was 44 years (range, 29-53) and the median time from diagnosis to transplant was 12 months (range, 6-144). Grade II-IV acute graft-versus-host disease (GvHD) occurred in six patients (35%). Severe grade III/IV GvHD developed in one patient (6%). Three patients died of therapy-related causes (17%). A complete remission (CR) with negative immunofixation after allogeneic transplantation was seen in eight of the evaluable patients (53%). After a median follow-up of 41 months (range, 8-84), the estimated overall survival at 6 years for all patients is 77% (CI 95%: 58-96%). The estimated progression-free survival at 6 years for all patients is 31% (CI 95%: 2-59%) and 46% (CI 95%: 9-83%) for patients with CR. In vivo T-cell depletion with ATG resulted in a low rate of severe GvHD with low treatment-related mortality, and a substantial number of long-term survivors.
Anti-tumor effects of anti-T-cell globulin. [2017]In vivo T-cell depletion using anti-T-cell antibodies is a standard procedure during allogeneic hematopoietic stem cell transplantation (allo-HSCT). Clinical data demonstrate that in vivo T-cell depletion with the anti-CD52 monoclonal antibody Alemtuzumab is associated with increased relapse rates of hematologic malignancies after allo-HSCT, underlining the importance of donor T cells for graft versus tumor activity. In contrast, recent results suggest that in vivo T-cell depletion with rabbit anti-T-cell globulin (ATG) Fresenius is not associated with tumor relapse after allo-HSCT, raising the possibility that ATG mediates antitumor effects. However, data on ATG's ability to bind to tumor cells and on its effect on the induction of antibody-dependent cellular cytotoxicity (ADCC) are lacking. We used ATG Fresenius, which contains polyclonal rabbit IgG directed against the human T-lymphoma cell line Jurkat, to study relevant mechanisms of ATG-mediated antitumor effects, including ADCC, complement-dependent cytotoxicity, and induction of apoptosis. Based on the knowledge that Jurkat cells aberrantly express myeloid markers and B-cell markers, we hypothesized that rabbit ATG Fresenius binds to a variety of hematologic malignancies. We found that ATG specifically binds to a variety of hematologic malignancies including acute myeloid leukemia and B-cell lymphoma in a concentration-dependent manner. We demonstrate that ATG mediates antitumor activity, including induction of ADCC, complement-dependent cytotoxicity, and apoptosis, toward different hematologic malignancies. Our results contribute to a better understanding of the effects of ATG on posttransplant immunology in patients undergoing allo-HSCT.
Prospective, Randomized, Double-Blind, Phase III Clinical Trial of Anti-T-Lymphocyte Globulin to Assess Impact on Chronic Graft-Versus-Host Disease-Free Survival in Patients Undergoing HLA-Matched Unrelated Myeloablative Hematopoietic Cell Transplantation. [2022]Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P
Antitumor effects of polyclonal antithymocyte globulins: focus on B-cell malignancies and multiple myeloma. [2009]Polyclonal antithymocyte globulins (ATGs) are used in organ and allogeneic stem cell transplantation mainly due to their immunomodulatory potential. Since ATGs contain antibodies against antigens expressed on various hematopoetic cells, it is not surprising that they induce cell death not only in healthy T-, B-, NK, and dendritic cells but also in malignant cells of lymphatic and to a lesser extent of myeloid lineage. The cytotoxic and antiproliferative effects of ATGs in malignant B-cells have been known for many years, without attracting clinical attention due to the advent of monoclonal antibodies like rituximab. Recent data indicate a potential role of ATGs in the therapy of multiple myeloma, a disease in which monoclonal serotherapy has been rather unsuccessful. This review discusses available data demonstrating the cytotoxic effects of ATGs and envisages a possible new role of these polyclonal antibodies in the therapy of hematological malignancies.
The impact of anti-thymocyte globulin on the outcomes of Patients with AML with or without measurable residual disease at the time of allogeneic hematopoietic cell transplantation. [2021]Measurable residual disease (MRD) status pre-allogeneic hematopoietic cell transplantation (allo-HCT) has been shown to predict transplant outcomes. We investigated the effect of Anti-Thymocyte Globulin (ATG) on acute myelogenous leukemia (AML) relapse by pretransplant MRD status. AML patients undergoing allo-HCT in first complete remission from either a matched sibling or unrelated donor during the 2006-2017 period were selected. Outcomes of 1509 patients (MRD+, n = 426) were studied. ATG was used in 561 (52%) and 239 (58%) patients within the MRD- and MRD+ cohorts, respectively. In MRD- patients, ATG did not affect relapse incidence (RI) (HR = 0.80, p = 0.17), but was associated with reduced incidence of grade II-IV acute GVHD, grade II-IV and chronic GVHD, reduced nonrelapse mortality (HR = 0.66, p = 0.05), improved leukemia-free survival (HR = 0.74, p = 0.02), overall survival (HR = 0.69, p = 0.01), and GVHD-relapse free survival (HR = 0.62, p < 0.01). In MRD+ patients, ATG was associated with a lower incidence of chronic GVHD (total, HR 0.56 p = 0.03; extensive, HR 0.40 P = 0.01), without an impact on other allo-HCT outcome parameters, including RI(HR = 1.02, p = 0.92). The use of ATG was associated with reduced risk for GVHD. ATG did not increase RI, even in high-risk AML patients who were MRD+ before allo-HCT.
Targeted dosing of anti-thymocyte globulin in adult unmanipulated haploidentical peripheral blood stem cell transplantation: A single-arm, phase 2 trial. [2023]Anti-thymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantation to prevent severe graft-versus-host disease (GVHD) and graft failure. However, overexposure to ATG may increase cytomegalovirus (CMV), Epstein-Barr virus (EBV) reactivation, non-relapse mortality, and disease recurrence. To investigate the optimal dosing of ATG, we established a targeted dosing strategy based on ATG concentration monitoring for haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). The aim of this phase 2 trial is to evaluate the safety and efficacy of the ATG-targeted dosing strategy in adult unmanipulated haplo-PBSCT. ATG was administered for 4 days (-5 days to -2 days) during conditioning. The ATG doses on -3 days and -2 days were adjusted by our dosing strategy to achieve the optimal ATG exposure. The primary endpoint was CMV reactivation on +180 days. Between December 2020 and January 2022, 66 haplo-PBSCT patients were enrolled and 63 of them were evaluable with a median follow-up of 632 days. The cumulative incidence of CMV reactivation was 36.7% and that of EBV was 58.7%. The 1-year disease-free survival was 82.5%, overall survival was 92.1%, and CD4+ T-cell reconstruction on +100 days was 76.8%. The most common severe regimen-associated toxicities (> grade 3) were infections (51.5%) and gastrointestinal toxicity (25.5%). A total of 102 haplo-PBSCT patients who received the conventional fixed ATG dose (cumulative 10 mg/kg) comprised historical control. The outcomes in historical control were inferior to those of phase 2 trial cohort (CMV reactivation: 70.8%, p
Serotherapy-Free Regimen Improves Non-Relapse Mortality and Immune Recovery Among the Recipients of ฮฑฮฒ TCell-Depleted Haploidentical Grafts: Retrospective Study in Childhood Leukemia. [2022]Depletion of ฮฑฮฒ T cells from the graft prevents graft-versus-host disease (GVHD) and improves the outcome of hematopoietic stem cell transplantation (HSCT) from haploidentical donors. Delayed recovery of adaptive immunity remains a problem, which can be approached by adoptive T-cell transfer. In a randomized trial, we have assessed the safety and efficacy of low-dose memory (CD45RA-depleted) donor lymphocytes (mDLI) after HSCT with ฮฑฮฒ T-cell depletion. Antithymocyte globulin (ATG) is viewed as an essential component of preparative regimen, critical for both prevention of graft failure and GVHD. Variable pharmacokinetics of ATG may significantly affect lymphocyte subpopulations after HSCT. To uncover the potential of mDLI, we replaced rabbit ATG with tocilizumab and abatacept. Here we compare post hoc the immune recovery and the key clinical outcomes, including nonrelapse mortality (NRM), overall- and event-free survival (OS and EFS), between the cohort enrolled in the prospective randomized trial and a historical cohort, comprised of patients grafted with a conventional ATG-based HSCT with ฮฑฮฒ T cell depletion. A cohort of 149 children was enrolled in the prospective trial and 108 patients were selected as historical controls from a prospectively populated database. Patient population was comprised of children with high-risk hematologic malignancies, with more than 90% represented by acute leukemia. Median age at enrollment was 8.8 years. In the prospective cohort 91% of the donors were haploidentical parents, whereas in the historical cohort 72% of the donors were haploidentical. Conditioning was based on either 12Gy total body irradiation or treosulfan. Thiotepa, fludarabine, bortezomib, and rituximab were used as additional agents. Patients in the historical cohort received rabbit ATG at 5 mg/kg total dose, while prospective cohort patients received tocilizumab at 8 mg /kg on day -1 and abatacept at 10 mg/kg on days 0, 7, 14, and 28. Patients in the prospective trial cohort were randomized 1:1 to receive mDLI starting on day 0, whereas 69% of historical cohort patients received mDLI after engraftment, as part of previous trials. Primary engraftment rate was 99% in the prospective cohort and 98% in the historical cohort. The incidence of grade II-IV aGVHD was 13% in the prospective cohort and 16 % in the control group. Chronic GVHD developed among 13% (historical) and 7% (prospective) cohorts (P = .07). The incidence of cytomegalovirus viremia was 51% in the prospective cohort arm and 54% in the historical control arm (p = ns). Overall, in the prospective cohort 2-year NRM was 2%, incidence of relapse was 25%, EFS was 71%, and OS was 80%, whereas in the historical cohort 2-year NRM was 13%, incidence of relapse was 19%, EFS was 67%, and OS was 76%, difference non-significant for relapse and survival. NRM was significantly improved in the ATG-free cohort (P = .002). Recovery of both ฮฑฮฒ- and ฮณฮด- T cells was significantly improved at days +30 and +60 after HSCT in recipients of ATG-free preparative regimens, as well as recovery of naรฏve T cells. Among the recipients of ฮฑฮฒ T-cell-depleted grafts, replacement of ATG with nonlymphodepleting abatacept and tocilizumab immunomodulation did not compromise engraftment and GVHD control and was associated with significantly lower NRM and better immune recovery early after HSCT.
Antithymocyte globulin for graft-versus-host disease prophylaxis: an updated systematic review and meta-analysis. [2020]Graft-versus-host disease (GVHD) remains a limiting factor for successful allogeneic hematopoietic cell transplantation (allo-HCT). Conflicting data exist on the benefit of ATG on post-transplant survival. We performed a systematic review of randomized controlled trials (RCTs) to assess benefits and harms of thymoglobulin and Fresenius (re-branded as Grafalon) ATG formulations in patients undergoing allo-HCT for a variety of hematologic malignancies and bone marrow failure syndromes. A comprehensive search of MEDLINE, EMBASE, and Cochrane Library was performed. Data on methodological quality, benefits, and harms were extracted for each trial and pooled under a random-effects model. Eight RCTs (1134 patients) met the inclusion criteria. Methodological quality ranged from moderate to very low. Pooled results showed no difference in overall survival (OS) with the use of ATG (hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.74-1.28; P = 0.83). ATG reduced grade II/III acute GVHD (risk ratio (RR) = 0.61; 95% CI = 0.48-0.77; P
Clinical outcomes with low dose anti-thymocyte globulin in patients undergoing matched unrelated donor allogeneic hematopoietic cell transplantation. [2021]Anti-thymocyte globulin (ATG) has been associated with decreased rates graft versus host disease (GVHD) but with a potential risk of increasing risk of infection and relapse. We retrospectively studied the impact of single dose low dose (2.5 mg/kg) ATG in patients undergoing allogenic hematopoietic cell transplantation (HCT) from 8/8 matched unrelated donors (MUD). Of the total 209 patients identified, 129 received ATG. At baseline, the ATG group had more intermediate and high disease risk index (DRI) (64.6% vs. 54.3%) (28.3% vs. 23.7%) p < .001, respectively, and who received reduced intensity or non-myeloablative conditioning (RIC) (69.0% vs. 47.5%, p .003). There was no significant difference in the overall survival (OS) HR = 1.3, 95% CI [0.99, 1.0], p = .350 or relapse-free survival (RFS) HR = 1.2, 95% CI [0.74, 1.8], p = .526 between the two groups. Patients receiving ATG had a lower incidence of chronic GVHD (cGVHD) (10.1% vs. 25%, p = .007) and less moderate to severe cGVHD (8.5% vs. 25%, p = .002). ATG was associated with a reduced incidence of moderate to severe cGVHD OR = 0.28, 95% CI [0.12, 0.61], p < .01. There was no difference in the incidence of Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) reactivation, CMV disease, invasive fungal infection, or grade III-IV acute GVHD (aGVHD). Our study shows that low dose ATG results in similar OS and RFS with lower rates of cGVHD. Additional prospective studies are needed to confirm these findings.
Antithymocyte Globulin Inhibits CD8+ T Cell Effector Functions via the Paracrine Induction of PDL-1 on Monocytes. [2023]Antithymocyte globulins (ATG) are T cell-depleting antibodies used in solid organ transplantation for induction therapy in sensitized patients with a high risk of graft rejection. Previously described effects besides the depletion of T cells have suggested additional modes of action and identified further cellular targets.
Objective regressions of T- and B-cell lymphomas in patients following treatment with anti-thymocyte globulin. [2007]We have conducted a clinical trial utilizing anti-thymocyte globulin (ATG) for the treatment of patients with non-Hodgkin's lymphomas. Six patients were treated; 50% reductions in tumor mass of short duration were observed in one patient with a T-cell lymphoma and two patients with B-cell lymphomas. In vitro assays have been performed in an attempt to study the reactivity and potential mechanism of antitumor action of the ATG. The ATG bound to essentially all normal blood mononuclear leukocytes as well as tumor cells from patients with T-, B-, or null cell lymphomas demonstrating its lack of specificity. Furthermore, complement-mediated lysis of normal mononuclear leukocytes, normal T- or B-cells, and tumor cells from two unresponsive patients were all comparable; moreover, since this lysis occurred only at concentrations of ATG that are not attainable in vivo, it is unlikely that complement-mediated cytotoxicity accounts for the responses observed. Peripheral blood lymphocyte counts and total erythrocyte rosettes did decrease during ATG treatment. Thus, objective tumor responses in both B- and T-cell non-Hodgkin's lymphomas can be achieved with a very nonspecific antiserum although significant toxicity resulted. Whether the magnitude or duration of response can be increased with monoclonal antibodies remains to be determined. Future success with serotherapy might require use of either a battery of different monoclonal antibodies or a single monoclonal antibody that can deliver radioisotopes, chemotherapy, or toxins to the tumor cells.