Stem Cell Transplant with T-allo10 Addback for Blood Diseases

Recruiting in Palo Alto (17 mi)

Overseen by Alice Bertaina, MD, PhD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Porteus, Matthew, MD

Disqualifiers: Pregnancy, Investigational agents, others

No Placebo Group

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.

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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.

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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.

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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.

Trial 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

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Lucile Packard Children's Hospital Palo Alto, CA

Who Is Running the Clinical Trial?

Porteus, Matthew, MD Lead Sponsor

Stanford University Lead Sponsor

Roncarolo, Maria Grazia, MD Lead Sponsor

California Institute for Regenerative Medicine (CIRM) Collaborator

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] Allogeneic peripheral blood stem cell transplantation with CD34+ cell-selection (CD34+-PBSCT) allows rapid hematologic engraftment with a reduction in graft-versus-host disease (GVHD), although concerns exist regarding the increased risk of tumor relapse associated with T-cell depletion of the graft. Delayed T-cell add-back (TCAB) after such transplants may restore the graft-versus-tumor effect while achieving a reduced early transplant-related mortality due to less GVHD in a group of patients at high risk of early death (i.e., age >= 45 years).

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

[Cell therapy for inherited diseases of the hematopoietic system]. [2007] Cell therapy was born in 1968 with the first allogeneic transplantation of hematopoietic stem cells for two immune deficiency disorders: the Wiskott-Aldrich syndrome and the Severe Combined ImmunoDeficiency (SCID). From this pioneering experience, thousands of patients affected with inherited or acquired diseases of the hematopoietic system have benefited from this therapeutic approach. Unfortunately, immunologic obstacles, represented by the compatibility in the major histocompatibility HLA system, still dictate today important limitations for a larger therapeutic utilization of hematopoietic stem cells (HSC). In this review, we have summarized the difficulties and the scientific advances leading us to improve the clinical results; the therapeutic research's track for primary immunodeficiencies is also discussed.

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] A recently occurring increase of the prevalence of haemoglobinopathies, β-thalassaemia major (TM) and sickle cell disease (SCD) over the last two decades in our country has generated new needs in terms of medical resources for both prevention and treatment of these patients. Allogeneic haematopoietic stem cell transplant (allo-HSCT) is a curative treatment available for patients who have severe haemoglobinopathies. The main objective of this study was to evaluate the results of allo-HSCT in paediatric patients with TM or SCD performed in paediatric hematopoietic transplant units within the Spanish Group of Bone Marrow Transplantation in Children (GETMON).

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

Immunological Outcome in Haploidentical-HSC Transplanted Patients Treated with IL-10-Anergized Donor T Cells. [2022] T-cell therapy after hematopoietic stem cell transplantation (HSCT) has been used alone or in combination with immunosuppression to cure hematologic malignancies and to prevent disease recurrence. Here, we describe the outcome of patients with high-risk/advanced stage hematologic malignancies, who received T-cell depleted (TCD) haploidentical-HSCT (haplo-HSCT) combined with donor T lymphocytes pretreated with IL-10 (ALT-TEN trial). IL-10-anergized donor T cells (IL-10-DLI) contained T regulatory type 1 (Tr1) cells specific for the host alloantigens, limiting donor-vs.-host-reactivity, and memory T cells able to respond to pathogens. IL-10-DLI were infused in 12 patients with the goal of improving immune reconstitution after haplo-HSCT without increasing the risk of graft-versus-host-disease (GvHD). IL-10-DLI led to fast immune reconstitution in five patients. In four out of the five patients, total T-cell counts, TCR-Vβ repertoire and T-cell functions progressively normalized after IL-10-DLI. These four patients are alive, in complete disease remission and immunosuppression-free at 7.2 years (median follow-up) after haplo-HSCT. Transient GvHD was observed in the immune reconstituted (IR) patients, despite persistent host-specific hypo-responsiveness of donor T cells in vitro and enrichment of cells with Tr1-specific biomarkers in vivo. Gene-expression profiles of IR patients showed a common signature of tolerance. This study provides the first indication of the feasibility of Tr1 cell-based therapy and paves way for the use of these Tr1 cells as adjuvant treatment for malignancies and immune-mediated disorders.

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

Do CAR-T and Allogeneic Stem Cell Transplant Both Have a Place in Lymphoid Neoplasms? [2023] Allogeneic stem cell transplantation (allo-SCT) represented the first immunotherapy to treat hematologic malignancies: it has been considered as a cure for the disease and never as an approach to extend the life of patients. The success of allo-SCT derives both from the ability to treat patients with intensive chemoradiotherapy and from the potent graft-versus-leukemia effects mediated by donor immunity. Although considerable progress has been made in the last years, significant barriers still remain in the form of disease relapse, graft-versus-host disease, infectious complications, and regimen-related toxicities. Moreover, the treatment of hematologic malignancies, particularly acute lymphoblastic leukemia and certain forms of lymphomas, has been revolutionized by the commercial introduction of genetically modified autologous T-lymphocyte therapy (CAR-T). Our review discusses current standards and the shifting paradigms in the indications for allo-SCT and the role of CAR-T cell therapy for lymphoid neoplasms.

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] Chimeric antigen receptor (CAR) therapy and hematopoietic stem cell transplantation (HSCT) are therapeutics for relapsed acute lymphocytic leukemia (ALL) that are increasingly being used in tandem. We identified a non-physiologic CD19+/CD3+ T-cell population in the leukapheresis product of a patient undergoing CAR T-cell manufacturing who previously received a haploidentical HSCT, followed by infusion of a genetically engineered T-cell addback product. We confirm and report the origin of these CD19+/CD3+ T cells that have not previously been described in context of CAR T-cell manufacturing. We additionally interrogate the fate of these CD19-expressing cells as they undergo transduction to express CD19-specific CARs.

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] Type 1 regulatory T (Tr1) cells are inducible, interleukin (IL)-10+FOXP3&#8722; regulatory T cells that can suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have optimized an in vitro protocol to generate a Tr1-enriched cell product called T-allo10, which is undergoing clinical evaluation in patients with hematological malignancies receiving a human leukocyte antigen (HLA)&#8211;mismatched allo-HSCT. Donor-derived T-allo10 cells are specific for host alloantigens, are anergic, and mediate alloantigen-specific suppression. In this study, we determined the mechanism of action of T-allo10 cells and evaluated survival of adoptively transferred Tr1 cells in patients. We showed that Tr1 cells, in contrast to the non-Tr1 population, displayed a restricted T cell receptor (TCR) repertoire, indicating alloantigen-induced clonal expansion. Tr1 cells also had a distinct transcriptome, including high expression of cytotoxic T lymphocyte&#8211;associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Blockade of CTLA-4 or PD-1/PD-L1 abrogated T-allo10&#8211;mediated suppression, confirming that these proteins, in addition to IL-10, play key roles in Tr1-suppressive function and that Tr1 cells represent the active component of the T-allo10 product. Furthermore, T-allo10&#8211;derived Tr1 cells were detectable in the peripheral blood of HSCT patients up to 1 year after T-allo10 transfer. Collectively, we revealed a distinct molecular phenotype, mechanisms of action, and in vivo persistence of alloantigen-specific Tr1 cells. These results further characterize Tr1 cell biology and provide essential knowledge for the design and tracking of Tr1-based cell therapies.

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

Graft-versus-host disease. [2021] Allogeneic haematopoietic stem-cell transplantation (SCT) is a curative therapy for haematological malignancies and inherited disorders of blood cells, such as sickle-cell anaemia. Mature alphabeta T cells that are contained in the allografts reconstitute T-cell immunity and can eradicate malignant cells in the recipient. Unfortunately, these T cells recognize the recipient as 'non-self' and employ a wide range of immune mechanisms to attack recipient tissues in a process known as graft-versus-host disease (GVHD). The full therapeutic potential of allogeneic haematopoietic SCT will not be realized until approaches to minimize GVHD, while maintaining the positive contributions of donor T cells, are developed. This Review focuses on research in mouse models pursued to achieve this goal.