TCRγδ T Cells + Blinatumomab for Blood Cancers

Overseen By Brandon Triplett, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: St. Jude Children's Research Hospital

Disqualifiers: Active malignancy, Uncontrolled infection, Pregnancy, 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

Compensation: Varies

Number of Visits: 2

170 Participants Needed

Trial Summary

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 TCRγδ T Cells + Blinatumomab for Blood Cancers?

Research shows that Blinatumomab, when used with donor lymphocyte infusions after stem cell transplantation, helped some patients with blood cancers achieve remission without causing severe side effects like Graft-versus-Host Disease (a condition where the donor cells attack the patient's body). This suggests that combining Blinatumomab with other treatments could be effective for certain blood cancers. ^{1 2 3 4 5}

What safety data exists for Blinatumomab in blood cancer treatments?

Blinatumomab has been used in patients with blood cancers and generally shows a low risk of severe side effects like Graft-versus-Host Disease (GvHD) when used after certain types of stem cell transplants. However, there are concerns about potential immune-related side effects, and more data is needed to fully understand its safety profile. ^{1 6 7 8 9}

How is the TCRγδ T Cells + Blinatumomab treatment for blood cancers different from other treatments?

This treatment is unique because it combines TCRγδ T cells, which can target cancer cells without needing a perfect match with the patient's immune system, with Blinatumomab, a drug that helps direct immune cells to attack cancer cells. This combination aims to enhance the anti-cancer effects while reducing the risk of complications like Graft-versus-Host Disease, which is common in other stem cell transplants. ^{1 10 11 12 13}

What is the purpose of this trial?

This study seeks to examine treatment therapy that will reduced regimen-related toxicity and relapse while promoting rapid immune reconstitution with limited serious graft-versus-host-disease (GVHD) and also improve disease-free survival and quality of life. The investigators propose to evaluate the safety and efficacy of selective naive T-cell depleted (by TCRɑβ and CD45RA depletion, respectively) haploidentical hematopoietic cell transplant (HCT) following reduced intensity conditioning regimen that avoids radiation in patients with hematologic malignancies that have relapsed or are refractory following prior allogeneic transplantation. PRIMARY OBJECTIVE: * To estimate engraftment by day +30 post-transplant in patients who receive TCRɑβ-depleted and CD45RA-depleted haploidentical donor progenitor cell transplantation following reduced intensity conditioning regimen without radiation. SECONDARY OBJECTIVES: * Assess the safety and feasibility of the addition of Blinatumomab in the early post-engraftment period in patients with CD19+ malignancy. * Estimate the incidence of malignant relapse, event-free survival, and overall survival at one-year post-transplantation. * Estimate incidence and severity of acute and chronic (GVHD). * Estimate the rate of transplant related mortality (TRM) in the first 100 days after transplantation.

Research Team

Brandon Triplett, MD

Principal Investigator

St. Jude Children's Research Hospital

Eligibility Criteria

This trial is for young people (≤21 years old) with certain blood cancers that didn't get better after a previous transplant. They need a family member who's at least a half-match as a donor, good heart and kidney function, not pregnant or breastfeeding, no other active cancers or uncontrolled infections, and able to perform some physical activities.

Inclusion Criteria

Left ventricular ejection fraction > 40%, or shortening fraction ≥ 25%.

My previous brain leukemia is treated and currently in remission.

Not pregnant as confirmed by negative serum or urine pregnancy test within 14 days prior to enrollment (if female).

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants receive a conditioning regimen of rabbit ATG, cyclophosphamide, fludarabine, thiotepa, melphalan, and rituximab prior to transplant

1-2 weeks

Transplantation

Infusion of TCRɑβ-depleted and CD45RA-depleted haploidentical donor progenitor cells, followed by G-CSF and blinatumomab

2 days

2 visits (in-person)

Engraftment Monitoring

Participants are monitored for engraftment by day +30 post-transplant

30 days

Follow-up

Participants are monitored for safety, effectiveness, and incidence of GVHD and relapse

1 year

Treatment Details

Interventions

• Blinatumomab
• TCRɑβ-depleted and CD45RA-depleted haploidentical donor progenitor cell transplantation

Trial Overview The study tests if T-cell depleted bone marrow transplants from half-matched family donors can help patients without using radiation. It also checks the safety of adding Blinatumomab post-transplant in CD19+ cancer cases to see if it improves survival rates and reduces complications like GVHD.

Participant Groups

Group I: Treatment Experimental Treatment 13 Interventions

Participants receive a conditioning regimen of antithymocyte globulin (rabbit), cyclophosphamide, mesna, fludarabine, thiotepa, tacrolimus (first 5 participants enrolled), sirolimus (used beginning with 6th enrolled participant), melphalan, rituximab. This is followed by HPC,A infusion (transplant), then by G-CSF and blinatumomab. Cells for infusion are prepared using the CliniMACS System.

Who Is Running the Clinical Trial?

St. Jude Children's Research Hospital

Lead Sponsor

Trials

451

Recruited

5,326,000+

Findings from Research

In a study of 168 patients with refractory/relapsed B-cell acute lymphoblastic leukemia, those who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) after CAR-T therapy had similar long-term survival rates compared to those who underwent haplo-HSCT after achieving minimal residual disease-negative complete remission from chemotherapy.

Patients who achieved a first complete remission (CR1) after chemotherapy had better overall survival and leukemia-free survival rates than those who had a second or more complete remission (≥CR2), highlighting the importance of achieving an earlier remission for better transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparable outcomes in patients with B-cell acute lymphoblastic leukemia receiving haploidentical hematopoietic stem cell transplantation: Pretransplant minimal residual disease-negative complete remission following chimeric antigen receptor T-cell therapy versus chemotherapy. Yang, TT., Meng, Y., Kong, DL., et al.[2022]

In a study of 197 patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia, blinatumomab demonstrated a significantly higher complete remission (CR) rate of 80.8% compared to 53.8% for conventional chemotherapy, indicating its greater efficacy.

Blinatumomab also led to a lower regimen-related mortality rate (1.9% vs. 40.4%) and improved overall survival at 3 years (33.2% vs. 15.4%), highlighting its safety and effectiveness as a treatment option before allogeneic hematopoietic cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Superior survival outcome of blinatumomab compared with conventional chemotherapy for adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia: a propensity score-matched cohort analysis. Yoon, JH., Kwag, D., Lee, JH., et al.[2023]

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]

Blinatumomab therapy before allogeneic hematopoietic cell transplantation (allo-HCT) in pediatric patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) effectively induced minimal residual disease (MRD)-negative remissions, leading to improved leukemia-free survival (LFS) compared to chemotherapy alone.

Importantly, blinatumomab did not increase the risk of post-transplant complications such as graft-versus-host disease (GVHD) or graft failure, suggesting it is a safe option for pre-HCT treatment in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Blinatumomab Therapy Is Associated with Favorable Outcomes after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients with B Cell Acute Lymphoblastic Leukemia. Llaurador, G., Shaver, K., Wu, M., et al.[2023]

Blinatumomab, a bispecific T-cell engager, has shown effectiveness in achieving negative minimal residual disease in patients with relapsed or refractory pre-B acute lymphoblastic leukemia after conventional chemotherapy.

In a case study, a patient with good health underwent successful allogenic stem cell transplantation after just one cycle of blinatumomab, suggesting its potential as an off-label treatment to enhance cytological remission before transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Blinatumomab as a bridge to trasplantation in refractory Philadelphia chromosome negative b-cell acute lymphoblastic leukemia: a case report]. Rodríguez-Ferreras, A., Zapico-García, I.[2019]

Gamma delta (γδ) T cells are a promising option for cancer immunotherapy, particularly for hematologic malignancies, due to their unique properties that allow them to target tumors without major histocompatibility complex (MHC) restrictions.

Their ability to act like antigen-presenting cells and their ease of expansion from peripheral blood make γδ T cells a strong candidate for allogeneic adoptive cellular therapy, potentially improving treatment outcomes for patients with difficult-to-treat cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic gamma delta T cells as adoptive cellular therapy for hematologic malignancies. Jhita, N., Raikar, SS.[2022]

A new protocol was developed to effectively expand γδ T cells from healthy donors for use in treating patients with acute myeloid leukemia (AML), achieving over 229,000-fold expansion of these cells.

The expansion process involves activating γδ T cells with FDA-approved zoledronic acid and interleukin-2, followed by purification and further expansion using engineered artificial antigen-presenting cells, making it a promising approach for cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expansion and Enrichment of Gamma-Delta (γδ) T Cells from Apheresed Human Product. Landin, AM., Cox, C., Yu, B., et al.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Blinatumomab Redirects Donor Lymphocytes against CD19+ Acute Lymphoblastic Leukemia without Relevant Bystander Alloreactivity after Haploidentical Hematopoietic Stem Cell Transplantation. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Comparable outcomes in patients with B-cell acute lymphoblastic leukemia receiving haploidentical hematopoietic stem cell transplantation: Pretransplant minimal residual disease-negative complete remission following chimeric antigen receptor T-cell therapy versus chemotherapy. [2022]

3. England pubmed.ncbi.nlm.nih.gov

A phase I/II trial of interleukin-15--stimulated natural killer cell infusion after haplo-identical stem cell transplantation for pediatric refractory solid tumors. [2020]

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

"Designed" grafts for HLA-haploidentical stem cell transplantation. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

CTLA4Ig-based reduced intensity conditioning and donor lymphocyte infusions for haploidentical transplantation in refractory aggressive B-cell lymphoma relapsing after an autograft: Early results from a pilot study. [2020]

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

Superior survival outcome of blinatumomab compared with conventional chemotherapy for adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia: a propensity score-matched cohort analysis. [2023]

7. Italy pubmed.ncbi.nlm.nih.gov

Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy. [2023]

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

Blinatumomab Therapy Is Associated with Favorable Outcomes after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients with B Cell Acute Lymphoblastic Leukemia. [2023]

9. Spain pubmed.ncbi.nlm.nih.gov

[Blinatumomab as a bridge to trasplantation in refractory Philadelphia chromosome negative b-cell acute lymphoblastic leukemia: a case report]. [2019]

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

Haplo graft engineering: sculpting to a T. [2021]

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

Allogeneic gamma delta T cells as adoptive cellular therapy for hematologic malignancies. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Influence of T cell depletion method on circulating gammadelta T cell reconstitution and potential role in the graft-versus-leukemia effect. [2019]

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

Expansion and Enrichment of Gamma-Delta (γδ) T Cells from Apheresed Human Product. [2021]