CD45RA Depleted Stem Cell Addback for Leukemia

Overseen By Linda Zitkus, BSN,RN

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Children's Hospital of Philadelphia

Must not be taking: Alemtuzumab

Disqualifiers: Hodgkin lymphoma, Non-Burkitt lymphoma, others

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

Compensation: Varies

Number of Visits: Unknown

100 Participants Needed

Trial Summary

What is the purpose of this trial?

The major morbidities of allogeneic hematopoietic stem cell transplant (HSCT) using donors that are not human leukocyte antigen (HLA) matched siblings are graft vs host disease (GVHD) and life- threatening infections. T cell receptor alpha beta (TCRαβ) T lymphocyte depletion and CD19+ B lymphocyte depletion of alternative donor hematopoietic stem cell (HSC) grafts is effective in preventing GVHD, but immune reconstitution may be delayed, increasing the risk of infections. The central hypothesis of this study is that an addback of CD45RO memory T lymphocytes, derived from a fraction of the original donor peripheral stem cell product depleted of CD45RA naïve T lymphocytes, will accelerate immune reconstitution and help decrease the risk of infections in TCRab/CD19 depleted PSCT.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the treatment CD45RA Depleted Stem Cell Addback for Leukemia?

Research shows that purging leukemia stem cells from transplants, similar to the CD45RA depletion method, can significantly reduce tumor cells and help in recovery after chemotherapy. Additionally, using specific markers like CD90 in stem cell transplants has been beneficial in purging leukemia cells, suggesting potential effectiveness for similar treatments. ^{1 2 3 4 5}

Is CD45RA Depleted Stem Cell Addback generally safe for humans?

Research on CD45RA-negative T cells, which are similar to CD45RA Depleted Stem Cell Addback, shows they can be used safely in humans without causing graft-versus-host disease (a condition where donor cells attack the recipient's body). In studies, these cells effectively controlled leukemia and infections without significant safety issues. ^{6 7 8 9 10}

How is the CD45RA Depleted Stem Cell Addback treatment different from other leukemia treatments?

The CD45RA Depleted Stem Cell Addback treatment is unique because it involves using stem cells that have been specifically depleted of CD45RA, a marker associated with certain immune cells, to reduce the risk of graft-versus-host disease (GVHD) while still effectively targeting leukemia. This approach aims to separate the beneficial anti-leukemia effects from the harmful immune reactions that can occur with other stem cell therapies. ^{8 11 12 13 14}

Research Team

Timothy Olson, MD, PhD

Principal Investigator

Children's Hospital of Philadelphia

Eligibility Criteria

This trial is for individuals up to 25 years old with conditions like primary immunodeficiency, various leukemias, bone marrow failure, and other related disorders. They should be in a state where a stem cell transplant could cure them and meet specific health standards set by the CHOP CTTS program.

Inclusion Criteria

My organs are healthy and I don't have infections.

I have taken a pregnancy test and it was negative.

My condition may be cured by a stem cell transplant from a donor.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Dose escalation study to determine the maximum tolerated cell dose of the CD45RA depleted addback using mismatched/haploidentical related donors

Up to 100 days

Phase 2 Treatment

Treatment with CD45RA depleted addback at maximum tolerated dose found in Phase 1 using mismatched related donors and unrelated donors

Concurrent with Phase 1

Follow-up

Participants are monitored for safety and effectiveness after treatment, including evaluation of immune reconstitution and graft vs host disease

Up to 2 years

Treatment Details

Interventions

• CD45RA Depleted Stem Cell Addback

Trial Overview The study tests adding back CD45RO memory T lymphocytes after depleting certain cells from donor stem cell grafts to prevent GVHD and infections post-transplant. It's determining the safest dose level that accelerates immune recovery without significant side effects.

Participant Groups

Group I: Phase 2:TCRab/CD19 depleted PSCT with CD45RA depleted addback using unrelated donors Experimental Treatment 1 Intervention

Stem cell source: mobilized PBSC Donor type: 9/10 or 10/10 matched unrelated donor Conditioning: disease specific SOC regimens

Group II: Phase 2:TCRab/CD19 depleted PSCT with CD45RA depleted addback at MTD found in phase 1 using MMRD Experimental Treatment 1 Intervention

Stem cell source: mobilized PBSC Donor type: \> or = 5/10 mismatched related donor Conditioning: disease specific SOC regimens

Group III: Phase 1:TCRab/CD19 depleted PSCT with CD45RA depleted addback using mismatched related donors (MMRD) Experimental Treatment 3 Interventions

Stem cell source: mobilized peripheral blood stem cells (PBSC) Donor type: \> or = 5/10 mismatched related donor Conditioning: disease specific standard of care (SOC) regimens

Who Is Running the Clinical Trial?

Children's Hospital of Philadelphia

Lead Sponsor

Trials

749

Recruited

11,400,000+

Findings from Research

CD19, CD20 chimeric antigen receptor T (CAR T) cell therapy has shown an impressive complete response rate of over 80% in treating acute lymphoblastic leukemia, indicating its high efficacy for this type of cancer.

In a review of 72 patients who received donor-derived CAR T cells, only 6.9% developed graft versus host disease, suggesting that this therapy has a low risk of this serious side effect while effectively preventing relapse and clearing minimal residual disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donor origin CAR T cells: graft versus malignancy effect without GVHD, a systematic review. Anwer, F., Shaukat, AA., Zahid, U., et al.[2022]

In a study involving nine patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL) and low donor chimerism after allogeneic stem cell transplant, autologous anti-CD19 CAR T cell therapy successfully restored complete donor chimerism in vitro after 12 days of culture.

The therapy showed strong cytotoxic effects against leukemia cells, with most patients experiencing mild cytokine release syndrome as the main adverse event, and two out of three treated patients achieving complete response without acute graft-versus-host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low Level Donor Chimerism of CD19 CAR-T Cells Returned to Complete Donor Chimerism in Patients with Relapse After Allo-Hematopoietic Stem Cell Transplant. Li, Q., Mu, J., Yuan, J., et al.[2022]

Allogeneic CAR-engineered CD45RA-negative T cells effectively target and kill CD19(+) MLL-rearranged leukemia cells, showing promise as a cancer treatment without causing graft-versus-host disease (GVHD).

In mouse models, these CAR(+)CD45RA(-) T cells not only reduced leukemia burdens and improved survival but also maintained their ability to respond to infections, suggesting they could be used safely in non-transplant settings as off-the-shelf therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor-redirected CD45RA-negative T cells have potent antileukemia and pathogen memory response without graft-versus-host activity. Chan, WK., Suwannasaen, D., Throm, RE., et al.[2021]

A unique population of CD19+/CD3+ T cells was identified in a patient undergoing CAR T-cell therapy after receiving haploidentical HSCT, suggesting that these cells originated from a previous treatment with a genetically modified T-cell product (RivoCel).

The presence of these CD19-expressing T cells may complicate CAR T-cell therapy, as they were eliminated during the CAR transduction process, indicating that using alternative markers instead of CD19 for tracking post-transplant T cells could be beneficial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of dual positive CD19+/CD3+ T cells in a leukapheresis product undergoing CAR transduction: a case report. Schultz, L., Patel, S., Davis, KL., et al.[2021]

CD19 CAR T-cell therapy has shown a high complete remission rate in pediatric acute lymphoblastic leukemia, highlighting its efficacy as a treatment for this type of cancer.

Despite its effectiveness, CD19 CAR T-cell therapy is associated with significant adverse reactions and an increased risk of cancer recurrence, necessitating further research into mechanisms of recurrence and strategies to mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cluster of differentiation 19 chimeric antigen receptor T-cell therapy in pediatric acute lymphoblastic leukemia. Fu, Z., Zhou, J., Chen, R., et al.[2020]

References

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

Positive selection for CD90 as a purging option in acute myeloid leukemia stem cell transplants. [2017]

2. England pubmed.ncbi.nlm.nih.gov

Continuous infusion of complement by an automated cell processor enhances cytotoxicity of monoclonal antibody sensitized leukemia cells. [2014]

3. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Impact of Leukemia Stem Cells Phenotype Expression on Response to Induction Therapy in Acute Myeloid Leukemia Patients. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Graft-versus-leukemia effect with a WT1-specific T-cell response induced by azacitidine and donor lymphocyte infusions after allogeneic hematopoietic stem cell transplantation. [2018]

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

Flow Cytometry to Estimate Leukemia Stem Cells in Primary Acute Myeloid Leukemia and in Patient-derived-xenografts, at Diagnosis and Follow Up. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Donor origin CAR T cells: graft versus malignancy effect without GVHD, a systematic review. [2022]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Low Level Donor Chimerism of CD19 CAR-T Cells Returned to Complete Donor Chimerism in Patients with Relapse After Allo-Hematopoietic Stem Cell Transplant. [2022]

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

Chimeric antigen receptor-redirected CD45RA-negative T cells have potent antileukemia and pathogen memory response without graft-versus-host activity. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Identification of dual positive CD19+/CD3+ T cells in a leukapheresis product undergoing CAR transduction: a case report. [2021]

10. Greece pubmed.ncbi.nlm.nih.gov

Cluster of differentiation 19 chimeric antigen receptor T-cell therapy in pediatric acute lymphoblastic leukemia. [2020]

11. England pubmed.ncbi.nlm.nih.gov

Mesenchymal stem cells suppress leukemia via macrophage-mediated functional restoration of bone marrow microenvironment. [2021]

12. China pubmed.ncbi.nlm.nih.gov

[Expression of CD45RA and CD45RO antigens and its implication in leukemias]. [2017]

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

Identification of therapeutic targets for quiescent, chemotherapy-resistant human leukemia stem cells. [2022]

14. Netherlands pubmed.ncbi.nlm.nih.gov

Proteomics identifies multipotent and low oncogenic risk stem cells of the spleen. [2021]