Dual-Targeted CAR-T Therapy for Leukemia

Recruiting at 4 trial locations

Overseen By Colleen Annesley, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Seattle Children's Hospital

Disqualifiers: CNS dysfunction, Pregnancy, Active infection, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

78 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients with relapsed or refractory leukemia often develop resistance to chemotherapy and some patients who relapse following CD19 directed therapy relapse with CD19 negative leukemia. For this reason, the investigators are attempting to use T-cells obtained directly from the patient, which can be genetically modified to express two chimeric antigen receptors (CARs). One is to recognize CD19 and the other is to recognize CD22, both of which are proteins expressed on the surface of the leukemic cell in patients with CD19+CD22+ leukemia. The CAR enables the T-cell to recognize and kill the leukemic cell through recognition of CD19 and CD22. This is a phase 1 study designed to determine the safety of the CAR+ T-cells and the feasibility of making enough to treat patients with CD19+CD22+ leukemia.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must be free from active GVHD and off immunosuppressive GVHD therapy for 4 weeks before enrolling, and at least 7 days post last chemotherapy and systemic corticosteroids administration.

What data supports the effectiveness of the dual-targeted CAR-T cell treatment for leukemia?

Research shows that dual-targeted CAR-T cells, which attack both CD19 and CD22, are effective in treating certain types of leukemia, with a high remission rate of 86% in a study of young patients. This approach helps prevent the cancer from escaping treatment by targeting two markers instead of one. ^{1 2 3 4 5}

Is dual-targeted CAR-T therapy for leukemia safe?

Dual-targeted CAR-T therapy, which targets both CD19 and CD22, has shown a favorable safety profile in clinical trials for leukemia and lymphoma. Most patients experienced mild to moderate side effects, with severe reactions being rare. No severe neurotoxicity was reported, and only one case of severe cytokine release syndrome occurred. ^{1 2 3 6 7}

How is Dual-Targeted CAR-T Therapy for Leukemia different from other treatments?

This treatment is unique because it uses CAR-T cells that target both CD19 and CD22 proteins on leukemia cells, potentially increasing effectiveness compared to therapies targeting only one protein. It is designed for patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), offering a novel approach for those who have not responded to standard treatments. ^{2 4 8 9 10}

Research Team

Colleen Annesley, MD

Principal Investigator

Seattle Children's Hospital

Eligibility Criteria

This trial is for patients under 31 years old with CD19+CD22+ leukemia that's resistant to standard treatments. They must have a life expectancy of at least 8 weeks, be free from severe infections or CNS dysfunction, not pregnant or breastfeeding, and able to tolerate cell collection procedures. Participants should also meet certain health and laboratory criteria.

Inclusion Criteria

I am under 31 years old.

Patients of childbearing/fathering potential must agree to use highly effective contraception from the time of initial T cell infusion through 12 months following the last T cell infusion

My cancer has returned or didn't respond to treatment, and I haven't had a stem cell transplant.

Exclusion Criteria

Presence of any concurrent medical condition that, in the opinion of the Principal Investigator, would prevent the patient from undergoing protocol-specified therapy

I have significant brain or nerve problems affecting my daily life.

I cannot undergo apheresis due to health reasons.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive genetically modified T-cells expressing CD19 and CD22 CARs to target leukemia cells

4 weeks

Multiple visits for T-cell infusion and monitoring

Follow-up

Participants are monitored for safety and effectiveness after CAR T-cell infusion

4 weeks

Regular visits for monitoring adverse events and treatment response

Treatment Details

Interventions

• Patient-derived CD19- and CD22-specific CAR-T Cell Immunotherapy

Trial Overview The study tests a new therapy using the patient's own T-cells genetically modified to target two proteins on leukemia cells (CD19 and CD22). It aims to see if this dual-targeting approach is safe and feasible in producing enough modified T-cells for treatment.

Participant Groups

Group I: Patient-derived CD19- and CD22 specific CAR v2 Experimental Treatment 1 Intervention

Patient-derived CD19-specific CAR also expressing an HER2t and CD22-specific CAR T-cells also expressing an EGFRt

Group II: Patient-derived CD19- and CD22 specific CAR v1 Experimental Treatment 1 Intervention

Patient-derived CD19-specific CAR also expressing an HER2t and CD22-specific CAR T-cells also expressing an EGFRt

Who Is Running the Clinical Trial?

Seattle Children's Hospital

Lead Sponsor

Trials

319

Recruited

5,232,000+

Findings from Research

The CD22/CD19 dual-targeting CAR-T-cell therapy showed a remarkable overall response rate of 97% and a complete remission rate of 93% in patients with relapsed/refractory acute lymphoblastic leukemia (ALL), based on a meta-analysis of 14 studies involving 405 patients.

For non-Hodgkin lymphoma (NHL), the therapy resulted in an overall response rate of 85% and a complete remission rate of 57%, with manageable side effects such as cytokine release syndrome occurring in 86% of patients, indicating both efficacy and tolerability of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and safety of CD22 and CD19 dual-targeting chimeric antigen receptor T-cell therapy in patients with relapsed or refractory B-cell malignancies: A meta-analysis. Nguyen, TT., Thanh Nhu, N., Chen, CL., et al.[2023]

In a phase II trial involving 225 patients aged 20 and under, coadministration of CD19- and CD22-CAR T cells resulted in a remarkable 99% complete remission rate for those with refractory B-acute lymphoblastic leukemia, with a 12-month event-free survival (EFS) rate of 73.5%.

While the treatment was effective, it was associated with significant side effects, including cytokine release syndrome in 88% of patients and CAR T-cell neurotoxicity in 20.9%, leading to three deaths, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Coadministration of CD19- and CD22-Directed Chimeric Antigen Receptor T-Cell Therapy in Childhood B-Cell Acute Lymphoblastic Leukemia: A Single-Arm, Multicenter, Phase II Trial. Wang, T., Tang, Y., Cai, J., et al.[2023]

In a phase 1 trial involving 15 pediatric and young adult patients with relapsed or refractory B-ALL, the dual-targeting CAR T-cell therapy AUTO3 demonstrated a favorable safety profile with no severe toxicities reported and an impressive remission rate of 86% one month post-treatment.

Despite the high initial remission rate, the one-year overall survival rate was 60% and event-free survival rate was 32%, indicating that improvements in the persistence of AUTO3 CAR T-cells are necessary to enhance long-term outcomes and prevent relapses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial. Cordoba, S., Onuoha, S., Thomas, S., et al.[2022]

The development of dual-targeting CAR T cells that target both CD19 and BAFF-R shows promise in overcoming treatment failures due to antigen loss in B-cell malignancies, specifically acute lymphoblastic leukemia (ALL).

In preclinical studies, these dual CAR T cells effectively eradicated both CD19- and BAFF-R-negative ALL variants in mice, demonstrating superior efficacy compared to single-target CAR T cells and suggesting potential for durable remissions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19/BAFF-R dual-targeted CAR T cells for the treatment of mixed antigen-negative variants of acute lymphoblastic leukemia. Wang, X., Dong, Z., Awuah, D., et al.[2023]

In a study of 16 patients with relapsed/refractory aggressive B-cell lymphoma, bispecific CAR T cells targeting both CD19 and CD22 showed a high efficacy, with 87.5% achieving an objective response and 62.5% achieving complete response.

The treatment demonstrated a favorable safety profile, with only one patient experiencing severe cytokine-release syndrome, and no cases of neurotoxicity, suggesting that this dual-targeted approach may be a safe and effective option for lymphoma therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19/CD22 Dual-Targeted CAR T-cell Therapy for Relapsed/Refractory Aggressive B-cell Lymphoma: A Safety and Efficacy Study. Wei, G., Zhang, Y., Zhao, H., et al.[2022]

CD19+ CAR T-cells have shown high effectiveness against various cancers, but their complete risk profile, including complications, was not fully understood during initial clinical trials.

Emerging evidence from post-approval studies reveals significant complications associated with CD19+ CAR T-cell therapy, such as cytokine release syndrome and neurotoxicity, indicating that these therapies can affect multiple organ systems and may lead to long-term health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications after CD19+ CAR T-Cell Therapy. Penack, O., Koenecke, C.[2020]

In a phase 1 trial of 53 adults with relapsed B-cell acute lymphoblastic leukemia, 83% achieved complete remission after receiving CD19-specific CAR T cells, indicating high initial efficacy.

Patients with a low disease burden before treatment experienced significantly longer overall survival (20.1 months) and fewer severe side effects, such as cytokine release syndrome, compared to those with a higher disease burden.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. Park, JH., Rivière, I., Gonen, M., et al.[2023]

The study found that Tn/mem-derived CD19-CAR T cells were safe and effective in treating adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL), with 87% of participants achieving complete remission or partial remission.

Among the 46 participants treated, those with Philadelphia-like ALL and extramedullary disease showed high response rates, and undergoing allogeneic hematopoietic cell transplantation after treatment significantly improved relapse-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Favorable Activity and Safety Profile of Memory-Enriched CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy in Adults with High-Risk Relapsed/Refractory ALL. Aldoss, I., Khaled, SK., Wang, X., et al.[2023]

References

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

Effectiveness and safety of CD22 and CD19 dual-targeting chimeric antigen receptor T-cell therapy in patients with relapsed or refractory B-cell malignancies: A meta-analysis. [2023]

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

Coadministration of CD19- and CD22-Directed Chimeric Antigen Receptor T-Cell Therapy in Childhood B-Cell Acute Lymphoblastic Leukemia: A Single-Arm, Multicenter, Phase II Trial. [2023]

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

CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial. [2022]

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

Dual CD19/CD22 CAR T Cells Show Feasibility in Pediatric/Young Adult B-ALL. [2022]

5. England pubmed.ncbi.nlm.nih.gov

CD19/BAFF-R dual-targeted CAR T cells for the treatment of mixed antigen-negative variants of acute lymphoblastic leukemia. [2023]

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

CD19/CD22 Dual-Targeted CAR T-cell Therapy for Relapsed/Refractory Aggressive B-cell Lymphoma: A Safety and Efficacy Study. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Complications after CD19+ CAR T-Cell Therapy. [2020]

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

Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. [2023]

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

Favorable Activity and Safety Profile of Memory-Enriched CD19-Targeted Chimeric Antigen Receptor T-Cell Therapy in Adults with High-Risk Relapsed/Refractory ALL. [2023]

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

Constant attack on T cell lymphomas. [2018]