Stem Cell Transplant with T-allo10 Addback for Blood Diseases

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Porteus, Matthew, MD

Disqualifiers: Pregnancy, Investigational agents, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8 weeks

22 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine the safety of a cell therapy, T-allo10, after αβdepleted-HSCT in the hopes that it will boost the adaptive immune reconstitution of the patient while sparing the risk of developing severe Graft-versus-Host Disease (GvHD). The primary objective of Phase 1a is to determine the recommended Phase 2 dose (RP2D) administered after infusion of αβdepleted-HSCT in children and young adults with hematologic malignancies. A Phase 1b extension will occur after dose escalation, enrolling at the RP2D for the T-allo10 cells determined in the Phase 1 portion to evaluate the safety and efficacy of infusion of T-allo10 after receipt of αβdepleted-HSCT. Additionally, Phase 1b aims to explore improvements in immune reconstitution. All participants on this study must be enrolled on another study: NCT04249830

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 Stem Cell Transplant with T-allo10 Addback for Blood Diseases?

Research shows that adding T-cells back after stem cell transplants can help restore the body's ability to fight tumors while reducing early death risks. Additionally, using IL-10-treated donor T-cells has shown promise in improving immune recovery without increasing the risk of harmful immune reactions. ^{1 2 3 4 5}

Is the Stem Cell Transplant with T-allo10 Addback generally safe for humans?

The T-allo10 cell therapy, used in combination with allogeneic stem cell transplantation, has shown potential in improving immune recovery without significantly increasing the risk of graft-versus-host disease (a condition where donor cells attack the recipient's body). Some patients experienced transient graft-versus-host disease, but overall, the therapy appears feasible and safe, with long-term survival and disease remission observed in some cases. ^{4 5 6 7 8}

What makes the Stem Cell Transplant with T-allo10 Addback treatment unique for blood diseases?

This treatment is unique because it combines allogeneic stem cell transplantation (a procedure where a patient receives blood-forming stem cells from a donor) with T-allo10 cell addback, which aims to enhance the graft-versus-tumor effect while reducing the risk of graft-versus-host disease (a condition where donor cells attack the recipient's body). This approach seeks to balance the benefits of donor immunity with minimized complications. ^{1 2 3 5 8}

Research Team

Alice Bertaina, MD, PhD

Principal Investigator

Associate Professor of Pediatrics, Stem Cell Transplantation

Eligibility Criteria

This trial is for children and adults aged over 1 month and under 45 years with life-threatening blood diseases, who've had a specific type of stem cell transplant (αβdepleted-HSCT) and are part of another study (NCT04249830). They must not have severe Graft-versus-Host Disease or be pregnant. Participants need to give consent personally or through a legal representative.

Inclusion Criteria

I am between 1 month and 45 years old and weigh at least 10 Kg.

Patients deemed eligible for allogeneic HSCT under the originating study, NCT 04249830

I have had a stem cell transplant and my bone marrow is making blood cells.

Exclusion Criteria

Not eligible to receive HSCT on NCT04249830

I or my donor cannot undergo an extra cell collection procedure before donating cells for the study.

You have taken part in another research study within the past month.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo αβ-depleted HSCT followed by T-allo10 cell infusion to determine the recommended Phase 2 dose (RP2D) and evaluate safety and efficacy

8 weeks

Multiple visits for treatment and monitoring

Follow-up

Participants are monitored for immune reconstitution and leukemia-free survival

60 days

Regular visits for monitoring immune reconstitution

Long-term follow-up

Participants are assessed for leukemia-free survival and disease relapse

1 year

Treatment Details

Interventions

• Allogeneic Stem Cell Transplant
• CliniMACS Prodigy System
• T-allo10 cells addback

Trial Overview The trial tests the safety of T-allo10 cells after an αβdepleted-HSCT in patients with hematologic malignancies. It aims to find the right dose that boosts immune recovery while minimizing severe GvHD risk. The study includes two phases: determining the optimal dose and then assessing its safety and effectiveness.

Participant Groups

Group I: Cohort 3 Experimental Treatment 3 Interventions

The participant will undergo a alpha-beta depleted stem cell transplant using donor cells. The participant's cells will then be manipulated via a T-allo10 cell addback to reach a dose level of 1 X 10\^6/kg

Group II: Cohort 2 Experimental Treatment 3 Interventions

The participant will undergo a alpha-beta depleted stem cell transplant using donor cells. The participant's cells will then be manipulated via a T-allo10 cell addback to reach a dose level of 3 X 10\^5/kg

Group III: Cohort 1 Experimental Treatment 3 Interventions

The participant will undergo a alpha-beta depleted stem cell transplant using donor cells. The participant's cells will then be manipulated via a T-allo10 cell addback to reach a dose level of 1 X 10\^5/kg

Allogeneic Stem Cell Transplant is already approved in United States, European Union for the following indications:

Approved in United States as Allogeneic Hematopoietic Stem Cell Transplantation for:

• Acute Leukemia
• Chronic Leukemia
• Lymphoma
• Multiple Myeloma
• Other hematologic malignancies

Approved in European Union as Allo-HSCT for:

• Acute Leukemia
• Chronic Leukemia
• Lymphoma
• Multiple Myeloma
• Other hematologic malignancies

Who Is Running the Clinical Trial?

Porteus, Matthew, MD

Lead Sponsor

Trials

2

Recruited

30+

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Roncarolo, Maria Grazia, MD

Lead Sponsor

Trials

2

Recruited

30+

California Institute for Regenerative Medicine (CIRM)

Collaborator

Trials

70

Recruited

3,300+

Findings from Research

In a pilot study involving 10 patients aged 45 and older with hematologic malignancies, CD34+ peripheral blood stem cell transplantation (CD34+-PBSCT) led to prompt engraftment and an acceptable level of transplant-related morbidity and mortality, despite some patients developing graft-versus-host disease (GVHD).

The study suggests that delaying T-cell add-back (TCAB) after CD34+-PBSCT may help restore the graft-versus-tumor effect while minimizing early transplant-related complications, indicating a potential strategy for improving outcomes in older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic peripheral blood stem cell transplantation with CD34+-cell selection and delayed T-cell add-back in adults. Results of a single center pilot study. Martino, R., Martín-Henao, G., Sureda, A., et al.[2006]

Cell therapy began in 1968 with the first successful transplantation of hematopoietic stem cells, which has since helped thousands of patients with immune disorders like Wiskott-Aldrich syndrome and Severe Combined ImmunoDeficiency (SCID).

Despite its success, the effectiveness of hematopoietic stem cell therapy is still limited by immunologic challenges related to HLA compatibility, which poses significant obstacles for broader application in treating various diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cell therapy for inherited diseases of the hematopoietic system]. Cavazzana-Calvo, M., Dal-Cortivo, L., André-Schmutz, I., et al.[2007]

In a study of 65 pediatric patients with β-thalassaemia major (TM) and sickle cell disease (SCD) who underwent allogeneic hematopoietic stem cell transplant (allo-HSCT), the three-year event-free survival rate was 81% for TM and 79% for SCD, indicating a high success rate for this curative treatment.

Overall survival rates were also promising, with 92% for TM and 85% for SCD, suggesting that allo-HSCT is an effective option for treating severe hemoglobinopathies in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation in pediatric patients with thalassemia and sickle cell disease: An experience of the Spanish Working Group for Bone Marrow Transplantation in Children (GETMON). Alonso, L., González-Vicent, M., Belendez, C., et al.[2020]

In a study involving 12 patients with high-risk hematologic malignancies, T-cell depleted haploidentical-HSCT combined with IL-10-pretreated donor T cells led to rapid immune reconstitution in five patients, with four achieving complete disease remission and remaining free of immunosuppression for over 7 years.

The use of IL-10-anergized donor T cells helped limit graft-versus-host disease (GvHD) while promoting tolerance, suggesting that Tr1 cell-based therapy could be a promising approach for treating malignancies and immune disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunological Outcome in Haploidentical-HSC Transplanted Patients Treated with IL-10-Anergized Donor T Cells. Bacchetta, R., Lucarelli, B., Sartirana, C., et al.[2022]

Allogeneic stem cell transplantation (allo-SCT) is a powerful treatment for hematologic malignancies, leveraging both intensive chemoradiotherapy and the immune response from donor cells to potentially cure diseases, though challenges like disease relapse and graft-versus-host disease remain significant.

The introduction of CAR-T cell therapy has transformed the treatment landscape for certain blood cancers, particularly acute lymphoblastic leukemia and specific lymphomas, indicating a shift in treatment paradigms and expanding options beyond traditional allo-SCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Do CAR-T and Allogeneic Stem Cell Transplant Both Have a Place in Lymphoid Neoplasms? Martino, M., Canale, FA., Naso, V., et al.[2023]

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]

The study developed a specialized cell product called T-allo10, enriched with Type 1 regulatory T (Tr1) cells, which can effectively suppress graft-versus-host disease (GvHD) in patients undergoing HLA-mismatched hematopoietic stem cell transplantation (allo-HSCT).

Tr1 cells showed a unique mechanism of action involving specific surface proteins (CTLA-4 and PD-1) that are crucial for their suppressive function, and these cells were found to persist in patients' blood for up to a year after treatment, indicating their potential for long-term therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alloantigen-specific type 1 regulatory T cells suppress through CTLA-4 and PD-1 pathways and persist long-term in patients. Chen, PP., Cepika, AM., Agarwal-Hashmi, R., et al.[2022]

Allogeneic haematopoietic stem-cell transplantation (SCT) is an effective curative treatment for blood-related diseases, but it can lead to graft-versus-host disease (GVHD) due to donor T cells attacking the recipient's tissues.

Research using mouse models is being conducted to find ways to reduce GVHD while still allowing donor T cells to effectively fight off cancer cells, which is crucial for maximizing the benefits of SCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Graft-versus-host disease. Shlomchik, WD.[2021]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Allogeneic peripheral blood stem cell transplantation with CD34+-cell selection and delayed T-cell add-back in adults. Results of a single center pilot study. [2006]

2. France pubmed.ncbi.nlm.nih.gov

[Cell therapy for inherited diseases of the hematopoietic system]. [2007]

3. Spain pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation in pediatric patients with thalassemia and sickle cell disease: An experience of the Spanish Working Group for Bone Marrow Transplantation in Children (GETMON). [2020]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Immunological Outcome in Haploidentical-HSC Transplanted Patients Treated with IL-10-Anergized Donor T Cells. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Do CAR-T and Allogeneic Stem Cell Transplant Both Have a Place in Lymphoid Neoplasms? [2023]

6. 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]

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

Alloantigen-specific type 1 regulatory T cells suppress through CTLA-4 and PD-1 pathways and persist long-term in patients. [2022]

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

Graft-versus-host disease. [2021]