Cell Depletion Therapy for Blood Cancers

Overseen By Meredith Beversdorf, RN

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Medical College of Wisconsin

Must not be taking: Chemotherapy, Radiation, Immunotherapy, others

Disqualifiers: Pregnancy, Active malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4-6 weeks

40 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 6 7 8 9}

How 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. ^{1 2 3 10 11}

Eligibility 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.

Exclusion Criteria

No suitable donor

Participating in a concomitant Phase 1 or 2 study involving treatment of disease

Pregnant or lactating patients are ineligible

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

Treatment Details

Interventions

• MCW Alpha/Beta T-Cell and B-Cell Depletion With Targeted ATG Dosing

Trial Overview 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.

Participant Groups

Group I: Alpha/Beta T cell depletion (TCD) plus CD19+ depletion Experimental Treatment 1 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, European Union for the following indications:

Approved in United States as Thymoglobulin for:

• Acquired aplastic anemia
• Renal allograft rejection
• Prevention of graft-versus-host disease

Approved in United States as Atgam for:

• Acquired aplastic anemia
• Renal allograft rejection

Approved in European Union as Grafalon for:

• Acquired aplastic anemia
• Renal allograft rejection
• Prevention of graft-versus-host disease

Who Is Running the Clinical Trial?

Medical College of Wisconsin

Lead Sponsor

Trials

645

Recruited

1,180,000+

Findings from Research

In vivo T-cell depletion using anti-thymocyte globulin (ATG) as part of a myeloablative conditioning regimen before allogeneic stem cell transplantation showed a low incidence of severe graft-versus-host disease (GvHD), with only 6% of patients experiencing grade III/IV GvHD.

The treatment resulted in a complete remission rate of 53% among evaluable patients, and after a median follow-up of 41 months, the overall survival rate was estimated at 77%, indicating both efficacy and safety in this patient population with advanced multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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). Kröger, N., Einsele, H., Wolff, D., et al.[2013]

In vivo T-cell depletion using rabbit anti-T-cell globulin (ATG) Fresenius during allogeneic hematopoietic stem cell transplantation (allo-HSCT) does not increase relapse rates of hematologic malignancies, suggesting it may have beneficial antitumor effects.

ATG Fresenius was found to specifically bind to various hematologic cancers, such as acute myeloid leukemia and B-cell lymphoma, and it mediates antitumor activity through mechanisms like antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-tumor effects of anti-T-cell globulin. Westphal, S., Brinkmann, H., Kalupa, M., et al.[2017]

In a phase III trial involving 254 patients undergoing hematopoietic cell transplantation, the use of anti-T-lymphocyte globulin (ATLG) significantly reduced the incidence of moderate-severe acute and chronic graft-versus-host disease (GVHD), but did not improve overall cGVHD-free survival rates compared to placebo.

Despite the reduction in GVHD, patients receiving ATLG experienced lower progression-free survival (47% vs. 65%) and overall survival (59% vs. 74%) rates, indicating that ATLG may not be beneficial in this context and further research is needed to clarify its role.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Soiffer, RJ., Kim, HT., McGuirk, J., et al.[2022]

Polyclonal antithymocyte globulins (ATGs) have immunomodulatory properties that can induce cell death in various hematopoietic cells, including malignant B-cells, making them a potential treatment option for hematological malignancies like multiple myeloma.

Recent findings suggest that ATGs may offer a new therapeutic avenue for multiple myeloma, especially since traditional monoclonal antibody treatments have had limited success in this disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor effects of polyclonal antithymocyte globulins: focus on B-cell malignancies and multiple myeloma. Ayuk, F., Zander, A., Kröger, N.[2009]

In a study of 1509 acute myelogenous leukemia (AML) patients undergoing allo-HCT, the use of Anti-Thymocyte Globulin (ATG) did not increase the risk of relapse, even in patients with measurable residual disease (MRD+), indicating its safety in high-risk groups.

ATG treatment was associated with significant benefits, including reduced incidence of acute and chronic graft-versus-host disease (GVHD), lower non-relapse mortality, and improved overall and leukemia-free survival in MRD- patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Nagler, A., Dholaria, B., Labopin, M., et al.[2021]

A targeted dosing strategy for anti-thymocyte globulin (ATG) in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) significantly reduced the rates of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation compared to conventional fixed dosing, with CMV reactivation dropping from 70.8% to 36.7%.

The phase 2 trial involving 63 evaluable patients showed improved overall survival (92.1%) and disease-free survival (82.5%) without increasing the incidence of graft-versus-host disease (GVHD), suggesting that optimized ATG dosing enhances patient outcomes and supports faster immune recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted dosing of anti-thymocyte globulin in adult unmanipulated haploidentical peripheral blood stem cell transplantation: A single-arm, phase 2 trial. Wang, H., Wang, N., Wang, L., et al.[2023]

In a study involving 149 children with high-risk hematologic malignancies, replacing rabbit antithymocyte globulin (ATG) with tocilizumab and abatacept during hematopoietic stem cell transplantation (HSCT) led to significantly lower nonrelapse mortality (NRM) rates compared to historical controls, indicating improved safety outcomes.

The use of memory donor lymphocytes (mDLI) in the ATG-free cohort did not compromise engraftment or control of graft-versus-host disease (GVHD), while also enhancing the recovery of T cell populations, suggesting a promising approach for improving immune recovery after HSCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serotherapy-Free Regimen Improves Non-Relapse Mortality and Immune Recovery Among the Recipients of αβ TCell-Depleted Haploidentical Grafts: Retrospective Study in Childhood Leukemia. Shelikhova, L., Glushkova, S., Nikolaev, R., et al.[2022]

A systematic review of 8 randomized controlled trials involving 1134 patients found that the use of ATG (thymoglobulin and Grafalon) did not improve overall survival after allogeneic hematopoietic cell transplantation, indicating that while ATG may help with GVHD, it does not necessarily lead to longer life.

ATG significantly reduced the incidence of both acute and chronic graft-versus-host disease without increasing the risk of non-relapse mortality, suggesting it is effective in managing GVHD complications during post-transplant recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antithymocyte globulin for graft-versus-host disease prophylaxis: an updated systematic review and meta-analysis. Kumar, A., Reljic, T., Hamadani, M., et al.[2020]

In a study of 209 patients undergoing allogenic hematopoietic cell transplantation, a single low dose of anti-thymocyte globulin (ATG) significantly reduced the incidence of chronic graft versus host disease (cGVHD) compared to those who did not receive ATG, with rates of 10.1% versus 25%.

Despite the reduction in cGVHD, the use of low dose ATG did not affect overall survival or relapse-free survival rates, indicating that it may be a safe option to minimize cGVHD without compromising patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes with low dose anti-thymocyte globulin in patients undergoing matched unrelated donor allogeneic hematopoietic cell transplantation. Mountjoy, L., Jain, T., Kunze, KL., et al.[2021]

Antithymocyte globulins (ATG) not only deplete T cells but also induce significant changes in immune cell activity, including increased levels of chemokines and cytokines like interferon-γ (IFN-γ) after ex vivo stimulation, suggesting additional immunosuppressive mechanisms.

ATG treatment enhances the expression of programmed death ligand 1 (PDL-1) on monocytes, which inhibits the proliferation and activity of activated CD8+ T cells through the JAK/STAT signaling pathway, representing a novel mode of action for ATG in preventing graft rejection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antithymocyte Globulin Inhibits CD8+ T Cell Effector Functions via the Paracrine Induction of PDL-1 on Monocytes. Copic, D., Direder, M., Klas, K., et al.[2023]

In a clinical trial involving six patients with non-Hodgkin's lymphomas, anti-thymocyte globulin (ATG) treatment led to a 50% reduction in tumor mass in three patients, indicating some efficacy against both T-cell and B-cell lymphomas.

Despite the observed tumor responses, ATG was found to be nonspecific and caused significant toxicity, suggesting that future treatments may benefit from using more targeted therapies like monoclonal antibodies to improve efficacy and reduce side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Objective regressions of T- and B-cell lymphomas in patients following treatment with anti-thymocyte globulin. Fisher, RI., Silver, BA., Vanhaelen, CP., et al.[2007]

References

1. England pubmed.ncbi.nlm.nih.gov

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]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Anti-tumor effects of anti-T-cell globulin. [2017]

3. United States pubmed.ncbi.nlm.nih.gov

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]

4. Germany pubmed.ncbi.nlm.nih.gov

Antitumor effects of polyclonal antithymocyte globulins: focus on B-cell malignancies and multiple myeloma. [2009]

5. England pubmed.ncbi.nlm.nih.gov

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]

6. United States pubmed.ncbi.nlm.nih.gov

Targeted dosing of anti-thymocyte globulin in adult unmanipulated haploidentical peripheral blood stem cell transplantation: A single-arm, phase 2 trial. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Serotherapy-Free Regimen Improves Non-Relapse Mortality and Immune Recovery Among the Recipients of αβ TCell-Depleted Haploidentical Grafts: Retrospective Study in Childhood Leukemia. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Antithymocyte globulin for graft-versus-host disease prophylaxis: an updated systematic review and meta-analysis. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Clinical outcomes with low dose anti-thymocyte globulin in patients undergoing matched unrelated donor allogeneic hematopoietic cell transplantation. [2021]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Antithymocyte Globulin Inhibits CD8+ T Cell Effector Functions via the Paracrine Induction of PDL-1 on Monocytes. [2023]

11. United States pubmed.ncbi.nlm.nih.gov

Objective regressions of T- and B-cell lymphomas in patients following treatment with anti-thymocyte globulin. [2007]