TCD HCT for Fanconi Anemia

Overseen By Margaret MacMillan, MD, Msc, FRCPC

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Masonic Cancer Center, University of Minnesota

Disqualifiers: Pregnancy, Uncontrolled infection, Malignant cancer, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a special type of stem cell transplant called T Cell Receptor α/β TCD HCT to assist individuals with Fanconi Anemia, a condition where the bone marrow fails to produce enough blood cells. The trial aims to enhance immune system recovery post-transplant and reduce the risk of serious infections. Treatment plans vary based on the patient's donor type and specific health conditions. This trial suits those diagnosed with Fanconi Anemia who experience severe blood issues, such as aplastic anemia or frequent infections. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant medical advancements.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that a special method for stem cell transplants, called T Cell Receptor α/β TCD, can lower the risk of graft-versus-host disease (GVHD). GVHD occurs when the donor's cells attack the recipient's body. This method improves results, especially when the donor isn't a perfect match.

Most research has involved children, so less information exists about its effectiveness in adults. While this method appears promising, detailed safety information for treating Fanconi Anemia with this approach isn't widely available yet. The current trial focuses on checking safety, indicating that the treatment shows potential but requires more study to confirm its tolerability. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for Fanconi Anemia because they explore different conditioning regimens for hematopoietic cell transplantation (HCT), which is a crucial therapy for this condition. Unlike traditional approaches that might rely heavily on high-dose chemotherapy and radiation, these regimens employ a mix of drugs like cyclophosphamide (CY), fludarabine (FLU), melphalan (MEL), and alemtuzumab to potentially reduce toxicity and improve outcomes. The use of T Cell Receptor α/β T Cell-Depleted (TCD) HCT is particularly promising as it aims to minimize graft-versus-host disease, a common complication in transplants. Moreover, the inclusion of rituximab and variations in the conditioning plans allow for more personalized treatment, accommodating different donor types and patient conditions, which could lead to better survival rates and quality of life for patients.

What evidence suggests that this trial's treatments could be effective for Fanconi Anemia?

Research has shown that a new treatment using T Cell Receptor α/β TCD HCT holds promise for Fanconi Anemia. In a study with 24 patients, this method helped prevent graft-versus-host disease, a complication where donor cells attack the patient's body. It achieves this by removing certain T cells that might cause problems, aiding better immune system recovery. This trial will explore various treatment plans incorporating T Cell Receptor α/β TCD HCT. For instance, Treatment Plan 1 includes TBI 300, CY, FLU, MP, and Rituximab, while Treatment Plan 2 uses CY, FLU, MP, and Rituximab without TBI. Another study found that using this treatment with imperfectly matched donors also led to better results. Although most data comes from children, recent progress indicates increasing success in adults. Overall, early results suggest this treatment could be a promising option for people with Fanconi Anemia. ^{1 2 3 4 6}

Who Is on the Research Team?

Margaret MacMillan, MD

Principal Investigator

Masonic Cancer Center, University of Minnesota

Are You a Good Fit for This Trial?

This trial is for patients with Fanconi anemia who have a suitable donor for blood cell transplant, are under 65 years old, and have good heart and lung function. They must not be pregnant or breastfeeding, have had solid tumor cancer in the last 2 years, or active infections. Participants need to agree to use contraception during treatment.

Inclusion Criteria

I am under 65 years old.

I have severe anemia, MDS, acute leukemia, or a high-risk genotype.

My liver, heart, and lung functions meet the required health standards.

Exclusion Criteria

I am not pregnant or breastfeeding and have a negative pregnancy test.

I have not had an uncontrolled infection in the last week.

I was diagnosed with a solid tumor cancer in the last 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

T cell receptor alpha/beta depletion (α/β TCD) peripheral blood stem cell transplantation

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Long-term follow-up

Monitoring for chronic graft versus host disease and overall survival

1 year

What Are the Treatments Tested in This Trial?

Interventions

• T Cell Receptor α/β TCD HCT

Trial Overview The study tests T cell receptor α/β depletion (α/β TCD) hematopoietic cell transplantation (HCT) in Fanconi anemia patients. It aims to reduce graft-versus-host disease without routine immune suppression drugs, hoping for faster immune recovery and fewer severe infections post-transplant.

How Is the Trial Designed?

Group I: Treatment Plan 5: CY, FLU, melphalan (MEL), and alemtuzumab. Experimental Treatment 4 Interventions

given to TBD patients with: * Early myelodysplastic features (with or without cytogenetic abnormalities) AND * Any donor type including haploidentical (4/8) to 8/8-HLA matched related donor, or 7-8/8 HLA-matched unrelated donor Based on historical numbers, it is expected approximately 2 patients would be treated per year. Statistical outcomes will be descriptive.

Group II: Treatment Plan 4: CY, FLU, and alemtuzumab Experimental Treatment 3 Interventions

given to TBD patients with: * Bone marrow failure AND * Any donor type including haploidentical (4/8) to 8/8-HLA matched related donor, or 7-8/8 HLA-matched unrelated donor Based on historical numbers, it is expected approximately 3 patients would be treated per year. Statistical outcomes will be descriptive.

Group III: Treatment Plan 3: BU, Cy, FLU, MP and Rituximab in patients with Fanconi Anemia Experimental Treatment 5 Interventions

Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type who cannot tolerate TBI * Patients with an HLA- identical sibling donor recipient and myelodysplastic features, MDS, or acute leukemia who cannot tolerate TBI * Biallelic mutations in FANCD1/BRCA2 who cannot receive TBI * Per treating physician preference

Group IV: Treatment Plan 2: CY, FLU, MP, Rituximab in patients with Fanconi Anemia Experimental Treatment 6 Interventions

Given to: • An HLA-identical sibling donor recipients with single or multi- lineage hematopoietic failure

Group V: Treatment Plan 1: TBI 300 , CY, FLU, MP, Rituximab in patients with Fanconi Anemia Experimental Treatment 7 Interventions

Given to: * Patients with an unrelated donor or HLA mismatched related donor, regardless of disease type OR * Patients with an HLA- identical sibling donor recipient and myelodysplastic features, MDS, or acute leukemia

T Cell Receptor α/β TCD HCT is already approved in European Union, United States for the following indications:

Approved in European Union as α/β TCD HCT for:

• Inherited Bone Marrow Failure Disorders
• Fanconi Anemia
• Primary Immunodeficiency Diseases

Approved in United States as α/β TCD HCT for:

• Inherited Bone Marrow Failure Disorders
• Fanconi Anemia
• Primary Immunodeficiency Diseases
• Nonmalignant Diseases

Who Is Running the Clinical Trial?

Masonic Cancer Center, University of Minnesota

Lead Sponsor

Trials

285

Recruited

15,700+

Published Research Related to This Trial

A case of high-risk myelodysplastic syndrome (HR-MDS) developed in a patient with relapsed diffuse large B cell lymphoma eight months after CAR T-cell therapy, highlighting a potential long-term risk associated with this treatment.

The patient's condition included chromosome 7 deletion and a RUNX1 mutation, suggesting that prior chemotherapy and possible immunosuppression from CAR T-cell therapy may contribute to the development of MDS, prompting a new multicenter study to explore these connections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High risk-myelodysplastic syndrome following CAR T-cell therapy in a patient with relapsed diffuse large B cell lymphoma: A case report and literature review. Accorsi Buttini, E., Farina, M., Lorenzi, L., et al.[2023]

In an analysis of 5249 adverse event reports related to CAR T-cell therapies, cytopenias were found to be a common side effect, with hematopoietic leukopenia being the most frequently reported adverse event (5.7%).

Tisagenlecleucel was associated with a significantly higher risk of specific cytopenias, particularly hematopoietic erythropenia, leukopenia, and thrombocytopenia, indicating that while CAR T-cell therapy is effective, it can lead to serious blood-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T-cell immunotherapies adverse events reported to FAERS database: focus on cytopenias. Gomez-Lumbreras, A., Mercadal Vilchez, S., Villa-Zapata, L., et al.[2023]

The study presents a novel method for purifying genetically modified T cells by altering just two amino acids in the TCRβ chain, which could enhance the efficacy and safety of αβTCR-based therapies.

Additionally, the development of an engineered antibody targeting a larger mutated interface in the TCRβ chain opens up new possibilities for selectively depleting engineered immune cells, potentially reducing side effects in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and modulation of anti-αβTCR antibodies and their respective binding sites at the βTCR chain to enrich engineered T cells. Kierkels, GJJ., van Diest, E., Hernández-López, P., et al.[2021]

A newly identified population of human T cells, called δ/αβ T cells, makes up about 50% of all Vδ1(+) T cells and can recognize both peptide and lipid-based antigens, expanding the diversity of the human immune response.

These δ/αβ T cells have a unique TCR structure that allows them to bind specifically to different lipid antigens presented by CD1d, indicating a novel mechanism of antigen recognition that combines features of both αβ and γδ T cell receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The molecular bases of δ/αβ T cell-mediated antigen recognition. Pellicci, DG., Uldrich, AP., Le Nours, J., et al.[2022]

γ/δ T cells, which make up 2-10% of T cells in human blood, have shown potential as beneficial effector cells in hematopoietic stem cell transplantation (HSCT), suggesting they could improve outcomes in allogeneic transplants.

Depleting α/β T lymphocytes from grafts can lower the risk of graft-versus-host disease (GvHD) while preserving γ/δ T cells and other beneficial cells, which may enhance engraftment and reduce infection risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transplantation in the onco-hematology field: focus on the manipulation of αβ and γδ T cells. Daniele, N., Scerpa, MC., Caniglia, M., et al.[2012]

The E6.R3 variant of Jurkat T cells has a deletion in the TCR-alpha transmembrane region that disrupts critical interactions with CD3 chains, leading to a lack of TCR membrane expression and signaling function.

Despite the defect, TCR alpha-chains in E6.R3 cells are fully glycosylated and processed normally, indicating that the absence of interaction with CD3 does not prevent their maturation in the Golgi apparatus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defective interactions between TCR chains and CD3 heterodimers prevent membrane expression of TCR-alpha beta in human T cells. Arnaud, J., Chenu, C., Huchenq, A., et al.[2017]

Two cases of Coombs-negative hemolytic anemia were identified in patients treated with CAR T-cell therapy for B-cell lymphoma, occurring 2-3 months post-treatment, highlighting a potential severe side effect of this therapy.

Monitoring for hemolytic anemia is recommended after CAR T treatment, as the observed decline in CAR T-cell levels correlated with rising hemoglobin levels, suggesting a possible link between CAR T-cell activity and the development of anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two Cases of Pancytopenia with Coombs-Negative Hemolytic Anemia after Chimeric Antigen Receptor T-Cell Therapy. Kiem, D., Leisch, M., Neureiter, D., et al.[2021]

In a study of 23 patients receiving allogeneic stem cell transplants, T cell depletion (TCD) strategies were found to slow the recovery of CD4 T cells, especially in those receiving fully TCD grafts, which persisted for the entire 12-month monitoring period.

Despite the slower recovery of CD4 cells, TCD recipients showed a more rapid recovery of natural killer (NK) cells, indicating that TCD may influence the reconstitution of different immune cell types post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of T cell depletion with Campath-1M on immune reconstitution after chemotherapy and allogeneic bone marrow transplant as treatment for leukaemia. Lowdell, MW., Craston, R., Ray, N., et al.[2017]

T-cell depletion of bone marrow grafts effectively reduces the risk of severe graft versus host disease (GVHD) after transplantation, with a pilot study showing only one case of acute severe GVHD among 21 patients.

The combination of T-cell depletion with reinfusion of CD2+ T-cells and an intensified conditioning regimen resulted in a 42.86% survival rate at 63 months, although there were significant risks associated with the procedure, including deaths related to the conditioning regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low dose T-cell lymphocyte infusion combined with marrow T-cell depletion as prophylaxis of acute graft vs host disease for HLA identical sibling bone marrow transplantation. Cahn, JY., Deconinck, E., Tiberghien, P., et al.[2019]

A unique population of human γδ T cells has been identified that can recognize the MHC-related protein 1 (MR1), indicating a new role for MR1 as a ligand for these T cells.

The study reveals a distinct binding mechanism of γδ T cell receptors (TCRs) to MR1, which differs from traditional TCR-MHC interactions, suggesting that γδ TCRs may have unique recognition parameters that could influence immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A class of γδ T cell receptors recognize the underside of the antigen-presenting molecule MR1. Le Nours, J., Gherardin, NA., Ramarathinam, SH., et al.[2021]

A systematic analysis of CAR T-cell therapy adverse events revealed 5,112 reports of hematotoxicity, highlighting significant under-reporting of severe conditions like hemophagocytic lymphohistiocytosis (HLH) and disseminated intravascular coagulation (DIC), which have high mortality rates of 69.9% and 59.6%, respectively.

The study identified 23 hematologic adverse events that were significantly over-reported compared to the general database, emphasizing the need for increased awareness and monitoring of these rare but potentially fatal toxicities in CAR T therapy patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy. Song, Z., Tu, D., Tang, G., et al.[2023]

In a phase 2 trial involving 24 patients with Fanconi anemia, 91.6% achieved sustained primary engraftment after receiving T-cell receptor αβ (TCRαβ+) and CD19+ cell-depleted hematopoietic stem cell transplantation, with quick recovery times for neutrophils and platelets.

The treatment was well tolerated with no fatal transplant-related toxicities, and after a median follow-up of 5.2 years, the overall survival rate was 100%, indicating high efficacy and safety of this transplantation method.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HLA-haploidentical TCRαβ+/CD19+-depleted stem cell transplantation in children and young adults with Fanconi anemia. Strocchio, L., Pagliara, D., Algeri, M., et al.[2022]

The study developed a new limiting dilution assay (LDA) to evaluate T cell depletion (TCD) using the monoclonal antibody T10B9, revealing that while T10B9 effectively targets T cells, it spares a significant portion of the TCR gamma delta + subset due to differential expression of the epitope.

Flow cytometry and blocking studies indicated that TCR gamma delta + T cells are less effectively lysed by complement when targeted by T10B9 compared to TCR alpha beta + T cells, suggesting that this subset may persist after TCD and could play a role in post-transplant clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new limiting dilution culture system for the detection of T cell subsets in T cell-depleted marrow grafts. Kawanishi, Y., Flomenberg, N., Cook-Craig, A., et al.[2006]

The study analyzed T cell clones (TCCs) from three individuals with similar HLA-Dw4 and -Dw14.1 molecules, revealing a diverse expression of 19 different V beta genes from 13 families, indicating a broad TCR repertoire.

For TCCs specific to PPD, there was a notable biased usage of the V beta 8 gene and a potential preference for a specific CDR3 motif, suggesting that certain TCR features may be favored in response to specific antigens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell receptor beta usage by 35 different antigen-specific T-cell clones restricted by HLA-Dw4 or -Dw14.1. Hansen, T., Qvigstad, E., Lundin, KE., et al.[2019]

Citations

1. withpower.com withpower.com/trial/phase-3-fanconi-syndrome-10-2018-7bad0

TCD HCT for Fanconi Anemia What data supports the effectiveness of the treatment T Cell Receptor α/β TCD HCT for Fanconi Anemia? A study involving 24 patients with Fanconi Anemia ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/33656536/

HLA-haploidentical TCRαβ+/CD19+-depleted stem cell ... We report on the outcome of 24 patients with Fanconi anemia (FA) lacking an HLA matched related or unrelated donor, given an HLA-haploidentical T-cell receptor ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4828537/

Recent advances in haploidentical hematopoietic stem cell ... The most recently developed approach using the negative depletion of αβ+ T cells improved the outcomes of T cell-depleted haploidentical transplant.

4. ashpublications.org ashpublications.org/blood/article/143/3/279/498045/TCR-CD19-cell-depleted-HLA-haploidentical

TCRαβ/CD19 cell–depleted HLA-haploidentical ... T-cell receptor (TCR)αβ/CD19 cell depletion has emerged as an effective graft manipulation strategy for preventing graft-versus-host disease ...

5. mdpi.com mdpi.com/2079-9721/13/7/195

Hematopoietic Stem Cell Transplant in Adult Patients with ... Data with TCD using αβ/CD19 depletion are intriguing but have been mainly limited to children. Although HSCT outcomes have been improving, the evidence to date ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S0006497123023248

TCRαβ/CD19 cell–depleted HLA-haploidentical ... T-cell receptor (TCR)αβ/CD19 cell depletion has emerged as an effective graft manipulation strategy for preventing graft-versus-host disease ...