CAR T-Cell Therapy for Leukemia

Overseen By Lindsay Danley

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dr. Melody Smith, MD, MS

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Other malignancy, Prior transplant, Infections, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new therapy for adults with B-cell acute lymphoblastic leukemia (ALL). Researchers aim to determine if using specially modified immune cells from a donor, known as CAR T-Cell Therapy, can safely combat the cancer without causing severe side effects. Participants may qualify if they have B-cell ALL that hasn't responded to treatment or has recurred and have a donor who meets specific medical criteria. The goal is to find a safe dose that enhances the fight against cancer while avoiding complications like graft-versus-host disease, where donor cells attack the patient’s body. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, it mentions that patients currently receiving corticosteroids or other immunosuppressive therapy are excluded, except for low doses of oral corticosteroids (10 mg/day or less). It's best to discuss your specific medications with the trial team.

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

Research shows that using specially modified immune cells from donors, called CD19/CD22-CAR T cells, is generally safe with manageable side effects. Studies have found that this treatment effectively targets certain blood cancers, like leukemia, without causing serious harm. Early results from studies testing different doses suggest that people tolerate the treatment well. While some mild side effects might occur, they are usually not serious. As this is an early-stage trial, the main goal is to ensure safety, and previous research provides some confidence in the treatment's safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard leukemia treatments, which often involve chemotherapy and stem cell transplants, this CAR T-cell therapy uses a unique approach by engineering donor-derived T-cells to specifically target and attack leukemia cells. These T-cells are modified with a bivalent lentiviral vector to express a chimeric antigen receptor (CAR) that simultaneously targets two proteins, CD19 and CD22, found on the surface of leukemia cells. This dual targeting could potentially increase the therapy's effectiveness and reduce the risk of cancer cells evading treatment. Researchers are excited because this method might offer a more precise and powerful attack on leukemia, with the possibility of long-lasting remission.

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

Research has shown that a new treatment combining CD19 and CD22 CAR T-cells may help treat B-cell acute lymphoblastic leukemia (B-ALL). One study found that this approach improved long-term survival for patients whose cancer returned after a stem cell transplant. Another study demonstrated that this treatment is highly effective and has manageable side effects for people with B-cell cancers. In this trial, participants will receive donor-derived CD19/CD22 CAR T-cells. Early results suggest that using T-cells from a donor with the CD19/CD22 CAR can be safe and effective. Additionally, Orca-T, another treatment option in this trial, might help prevent a condition where donor cells attack the patient's body. These positive findings support the potential of these therapies to aid those with B-ALL. ^{1 3 4 6 7}

Who Is on the Research Team?

Lori Muffly, MD

Principal Investigator

Stanford University

Are You a Good Fit for This Trial?

Adults aged 18-65 with B-cell Acute Lymphoblastic Leukemia who have a matched related donor for T cell and stem cell grafts. Participants should have high-risk ALL features or persistent disease after treatment, adequate organ function, and no history of certain infections or autoimmune CNS involvement. They must not be pregnant, breastfeeding, or unwilling to use birth control post-treatment.

Inclusion Criteria

I can take care of myself but may not be able to do heavy physical work.

I have active acute lymphoblastic leukemia.

My heart, liver, kidneys, lungs, and brain are functioning well.

Exclusion Criteria

I have a history of HIV, Hepatitis B, or Hepatitis C.

I haven't had a heart attack or other major heart issues in the last year.

Any medical condition that in the judgement of the investigator is likely to interfere with assessment of safety or efficacy of study treatment

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Myeloablative Conditioning

Participants undergo a myeloablative conditioning regimen to prepare for the infusion of donor-derived CD19/CD22-CAR T cells

1-2 weeks

Treatment

Participants receive donor-derived CD19/CD22-CAR T cells and Orca-T infusion

6 weeks

Multiple visits for monitoring and infusion

Follow-up

Participants are monitored for safety, engraftment, and disease progression

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Allogeneic donor-derived T-cells transduced with bivalent lentiviral vector (CD19/CD22-BBz) chimeric antigen receptor (CAR)
• Orca-T

Trial Overview The trial tests the safety of CD19/CD22-CAR T cells from donors following myeloablative conditioning and Orca-T in adults with B-cell ALL. It aims to enhance leukemia defense without increasing acute GVHD (graft versus host disease) or graft failure.

How Is the Trial Designed?

Group I: Dose escalation Experimental Treatment 2 Interventions

Bayesian dose escalation design for the dosing of the donor CD19/CD22-CAR T cells

Allogeneic donor-derived T-cells transduced with bivalent lentiviral vector (CD19/CD22-BBz) chimeric antigen receptor (CAR) is already approved in United States, European Union for the following indications:

Approved in United States as Allogeneic CD19/CD22-CAR T cells for:

• B-cell Acute Lymphoblastic Leukemia (ALL)

Approved in European Union as Allogeneic CD19/CD22-CAR T cells for:

• B-cell Acute Lymphoblastic Leukemia (ALL)

Who Is Running the Clinical Trial?

Dr. Melody Smith, MD, MS

Lead Sponsor

Trials

1

Recruited

20+

Crystal Mackall, MD

Lead Sponsor

Trials

6

Recruited

240+

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Melody Smith

Lead Sponsor

American Society of Hematology

Collaborator

Trials

14

Recruited

20,800+

National Marrow Donor Program

Collaborator

Trials

63

Recruited

202,000+

Orca Biosystems, Inc.

Industry Sponsor

Trials

8

Recruited

750+

Published Research Related to This Trial

In a study involving 9 patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL) after stem cell transplantation, donor-derived CD19 CAR-T cell therapy resulted in a complete remission rate of 100% within 28-42 days post-infusion, with 6 patients remaining leukemia-free after a median follow-up of 25.1 months.

While the therapy was effective, all patients experienced cytokine release syndrome (CRS) and some developed neurotoxicity and graft-versus-host disease (GVHD), indicating that while side effects were manageable, they are an important consideration in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Allogeneic donor-derived CD19 CAR-T therapy of relapsed B-cell acute lmphoblastic leukemia after allogeneic hematopoietic stem cell transplantation]. Ma, RZ., He, Y., Yang, DL., et al.[2022]

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]

In a pilot clinical trial involving 9 patients with relapsed or chemotherapy-refractory B-cell acute lymphocytic leukemia (B-ALL), genetically modified T cells targeting the CD19 antigen showed a 56% overall survival rate at 18 weeks.

The study demonstrated that donor-derived anti-CD19 CAR T cells can lead to significant regression of both hematopoietic and extramedullary B-ALL, although some patients experienced grade 2-3 graft-versus-host disease (GVHD) after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerance and efficacy of autologous or donor-derived T cells expressing CD19 chimeric antigen receptors in adult B-ALL with extramedullary leukemia. Dai, H., Zhang, W., Li, X., et al.[2021]

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]

Genetically engineered T cells that express a CD19-specific chimeric immunoreceptor can effectively target and eradicate B-lineage malignancies, showcasing a promising approach in cancer treatment.

Using these modified T cells can potentially avoid the complications of graft-versus-host disease (GVHD) associated with traditional donor-derived T cell therapies, enhancing the safety and efficacy of the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and application of CD19-specific T cells for adoptive immunotherapy of B cell malignancies. Cooper, LJ., Al-Kadhimi, Z., DiGiusto, D., et al.[2007]

CRISPR/Cas9-mediated knockout of the T-cell receptor (TCR) in anti-CD19 CAR T cells significantly reduces the risk of graft-versus-host disease while maintaining strong antileukemic activity against B-precursor acute lymphoblastic leukemia (ALL) in a patient-derived xenograft model.

However, while TCR-KO CAR T cells show high functionality and reduced alloreactivity, the presence of the endogenous TCR enhances the long-term persistence and effectiveness of T cells in controlling leukemia, suggesting a trade-off between safety and durability of response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Endogenous TCR promotes in vivo persistence of CD19-CAR-T cells compared to a CRISPR/Cas9-mediated TCR knockout CAR. Stenger, D., Stief, TA., Kaeuferle, T., et al.[2022]

Allogeneic CAR-T cells targeting CD19 have shown effective treatment outcomes in children and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL), achieving complete remission in all patients studied, with a median follow-up of 12 months.

The safety profile of these donor-derived CAR-T cells was comparable to that of autologous CAR-T cells, with manageable side effects such as mild cytokine release syndrome and low-grade neurotoxicity, indicating a promising alternative for patients unable to access autologous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic, donor-derived, second-generation, CD19-directed CAR-T cells for the treatment of pediatric relapsed/refractory BCP-ALL. Del Bufalo, F., Becilli, M., Rosignoli, C., et al.[2023]

A new strategy has been developed to create virus-specific T cells from donor blood that can be genetically modified to target leukemia cells, specifically those expressing the CD19 marker, which could help prevent or treat leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

The modified T cells showed similar activation and effectiveness in killing leukemia cells when stimulated through either the chimeric antigen receptor (CAR) or their natural T cell receptor (TCR), indicating that this approach could provide a robust method for targeted leukemia therapy while minimizing the risk of graft-versus-host disease (GVHD).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells. Terakura, S., Yamamoto, TN., Gardner, RA., et al.[2023]

BiCAR-T cells, which target both CD19 and CD22, demonstrated significant anti-tumor effects in both laboratory and animal models, suggesting enhanced efficacy compared to single-target CAR-T therapies.

This dual targeting approach may help prevent relapse in B-cell acute lymphoblastic leukemia (B-ALL) by reducing the risk of immune escape due to loss of the targeted antigens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering Novel CD19/CD22 Dual-Target CAR-T Cells for Improved Anti-Tumor Activity. Zeng, W., Zhang, Q., Zhu, Y., et al.[2022]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/679/530563/Safe-and-Effective-Combination-of-Donor-Derived

Safe and Effective Combination of Donor-Derived, Allogeneic ... Here, we report clinical outcomes of the initial dose escalation of donor-derived, allogeneic CD19/CD22-CAR T cells with Orca-T in our novel ...

2. haematologica.org haematologica.org/article/view/11872

Five-year outcome of CD19 followed by CD22 chimeric ... Our study revealed that, in post-HCT relapsed B-ALL patients, the combination of CD19 and CD22 CAR T-cell therapy significantly improved long-term survival.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10557829/

Effectiveness and safety of CD22 and CD19 dual‐targeting ... Our meta‐analysis demonstrated that the CD22/CD19 dual‐targeting CAR‐T‐cell strategy has high efficiency with tolerable adverse effects in B‐cell malignancies.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124034268

Safe and Effective Combination of Donor-Derived ... Here, we report clinical outcomes of the initial dose escalation of donor-derived, allogeneic CD19/CD22-CAR T cells with Orca-T in our novel ...

5. ehoonline.biomedcentral.com ehoonline.biomedcentral.com/articles/10.1186/s40164-024-00593-5

Prominent efficacy and good safety of sequential CD19 ... This study aimed to evaluate the efficacy and safety of sequential CD19 and CD22 CAR-T cell therapy in adult patients with R/R B-ALL between ...

6. reporter.nih.gov reporter.nih.gov/project-details/11197508

Donor Derived CD19/CD22 CAR T Cells as ... - NIH RePORTER A clinical study of an autologous bispecific CAR targeting CD19 and CD22 (CD19-22.BB.z-CAR = CAR19/22) induced remission in patients with B-cell acute ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05507827

NCT05507827 | Myeloablative Conditioning Orca-T & ... To assess the safety of administering allogenic, donor-derived CD19/CD22-CAR T cells that meet established release specifications in adults with B-cell ALL ...