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

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial is testing a treatment that uses special immune cells from a donor, modified to target and kill cancer cells, in adults with a specific type of blood cancer. These cells act like guided missiles, finding and destroying cancer cells by recognizing specific markers.

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 CAR T-Cell Therapy for Leukemia safe for humans?

CAR T-Cell Therapy for Leukemia has shown a high remission rate with manageable side effects such as cytokine release syndrome (a condition where the immune system releases too many proteins into the blood too quickly) and immune effector cell-associated neurotoxicity syndrome (a temporary condition affecting the nervous system). Some patients experienced graft-versus-host disease (a condition where donor cells attack the recipient's body), but it was controllable with treatment. ^{1 2 3 4 5}

How is the CAR T-cell therapy for leukemia different from other treatments?

This treatment uses donor-derived T-cells that are genetically modified to target two specific proteins (CD19 and CD22) on leukemia cells, which is unique because it combines targeting of two antigens to potentially improve effectiveness and reduce relapse. Additionally, these T-cells are engineered to minimize the risk of graft-versus-host disease (GVHD), a common complication in treatments involving donor cells. ^{1 3 6 7 8}

What data supports the effectiveness of the treatment Allogeneic donor-derived T-cells transduced with bivalent lentiviral vector (CD19/CD22-BBz) chimeric antigen receptor (CAR) for leukemia?

Research shows that CAR T-cell therapy targeting CD19 and CD22 antigens can effectively kill leukemia cells and reduce the risk of cancer relapse. Studies have demonstrated that these engineered T-cells can significantly reduce leukemia burdens and improve survival rates in animal models, and they have shown promising results in clinical trials for B-cell malignancies. ^{1 2 6 8 9}

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

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]

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]

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]

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]

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]

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 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]

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]

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]

Citations

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

Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells. [2023]

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

Development and application of CD19-specific T cells for adoptive immunotherapy of B cell malignancies. [2007]

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

Engineering Novel CD19/CD22 Dual-Target CAR-T Cells for Improved Anti-Tumor Activity. [2022]

4. England 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. [2021]

5. United States 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. [2021]

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. China 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]. [2022]

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

Allogeneic, donor-derived, second-generation, CD19-directed CAR-T cells for the treatment of pediatric relapsed/refractory BCP-ALL. [2023]

9. United States 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. [2022]