CAR T-Cell Therapy for Acute Lymphoblastic Leukemia

Recruiting at 2 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Seattle Children's Hospital

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

Compensation: Varies

Number of Visits: Unknown

Duration: 2 months

167 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients with relapsed or refractory leukemia often develop resistance to chemotherapy. For this reason, we are attempting to use T cells obtained directly from the patient, which can be genetically modified to express a chimeric antigen receptor (CAR). The CAR enables the T cell to recognize and kill the leukemic cell through the recognition of CD19, a protein expressed of the surface of the leukemic cell in patients with CD19+ leukemia. This is a phase 1/2 study designed to determine the maximum tolerated dose of the CAR+ T cells as well as to determine the efficacy. The phase 1 cohort is restricted to those patients who have already had an allogeneic hematopoietic cell transplant (HCT). The phase 2 is open to all patients regardless of having a history of HCT.

Will I have to stop taking my current medications?

The trial requires that you stop taking systemic corticosteroids (unless it's a small dose for hormone replacement) at least 7 days before enrolling. You also need to be off immunosuppressive therapy for graft-versus-host disease (GVHD) for 4 weeks before enrolling. Other medications might need to be paused, but the protocol doesn't specify all details.

What data supports the effectiveness of the treatment CAR T-Cell Therapy for Acute Lymphoblastic Leukemia?

Research shows that CD19-specific CAR T cells, which are part of this treatment, lead to high initial response rates and long-term remissions in some patients with relapsed B-cell acute lymphoblastic leukemia (ALL). Additionally, studies indicate that these CAR T cells are effective and safe for patients with high-risk or relapsed ALL. ^{1 2 3 4 5}

Is CAR T-Cell Therapy safe for humans?

CAR T-Cell Therapy for acute lymphoblastic leukemia has shown some safety concerns, including severe side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). However, studies have generally found it to be safe enough for use, with ongoing efforts to reduce these risks. ^{1 2 3 5 6}

What makes CAR T-Cell Therapy for Acute Lymphoblastic Leukemia unique?

This treatment uses genetically modified T cells to specifically target and attack cancer cells expressing the CD19 protein, offering a novel approach for patients with relapsed or refractory B-cell acute lymphoblastic leukemia. It has shown high initial response rates and potential for long-term remission, unlike traditional chemotherapy. ^{1 2 3 7 8}

Research Team

Colleen Annesley, MD

Principal Investigator

Seattle Children's Hospital

Eligibility Criteria

This trial is for young patients (12 months to less than 27 years old) with CD19+ leukemia that's come back or hasn't responded to treatment. They must weigh at least 10kg, have no severe active infections, and not have had certain prior treatments like genetically modified cell therapy. Those who've had a transplant can join phase 1; others may join phase 2.

Inclusion Criteria

Patient must have documented negative HIV antigen and antibody, Hepatitis B surface antigen, and Hepatitis C antibody within 3 months prior to enrollment

I haven't had active graft-versus-host disease or been on GVHD treatment for 4 weeks.

I have recovered from the side effects of my previous cancer treatments.

Exclusion Criteria

I do not have a severe infection or fever above 38.2 C recently.

Patients must NOT have any concurrent medical condition that, in the opinion of the PI or designee, would prevent the patient from undergoing protocol-based therapy

Patients with a primary immunodeficiency/ bone marrow failure syndrome are excluded from this trial

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Apheresis and T Cell Generation

Subjects undergo apheresis to obtain T cells, which are then genetically modified to express CD19 CAR and expanded over a three-week period.

3 weeks

Treatment

Participants receive an infusion of CAR+ T cells following lymphodepletion, if necessary.

2 months

Intense follow-up with serial blood testing and disease status re-evaluation

Follow-up

Participants are monitored for safety and effectiveness after treatment, with bi-annual follow-ups for 5 years and annual follow-ups for 10 additional years.

15 years

Treatment Details

Interventions

• Patient Derived CD19 specific CAR T cells also expressing an EGFRt

Trial Overview The study tests CAR T cells made from the patient's own immune cells, engineered to target CD19 on leukemia cells. It aims to find the safest dose and see how well it works. Phase 1 involves post-transplant patients; phase 2 is open more broadly.

Participant Groups

Group I: Phase 2 Experimental Treatment 1 Intervention

The phase 2 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1 x 10\^6 CAR T cells/kg following lymphodepletion if indicated.

Group II: Phase 1 - Cohort 1F2 Experimental Treatment 1 Intervention

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1x10\^6 CAR T cells/kg following prescribed lymph-depletion with fludarabine and cyclophosphamide

Group III: Phase 1 - Cohort 1F1 Experimental Treatment 1 Intervention

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 5x10\^5 CAR T cells/kg following prescribed lymph-depletion with fludarabine and cyclophosphamide

Group IV: Phase 1 - Cohort 1D Experimental Treatment 1 Intervention

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1x10\^7 CAR T cells/kg

Group V: Phase 1 - Cohort 1C Experimental Treatment 1 Intervention

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 5x10\^6 CAR T cells/kg

Group VI: Phase 1 - Cohort 1B Experimental Treatment 1 Intervention

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 1x10\^6 CAR T cells/kg

Group VII: Phase 1 - Cohort 1A Experimental Treatment 1 Intervention

This phase 1 cohort will receive Patient Derived CD19 specific CAR T cells at a dose of 5x10\^5 CAR T cells/kg

Who Is Running the Clinical Trial?

Seattle Children's Hospital

Lead Sponsor

Trials

319

Recruited

5,232,000+

Findings from Research

In a study of 15 patients with B cell acute lymphoblastic leukemia (B-ALL) who experienced extramedullary relapse, CD19 CAR-T cell therapy resulted in a high overall response rate of 93.3%, with 73.3% achieving complete response and a median duration of response of 6 months.

The therapy was associated with manageable adverse effects, including cytokine release syndrome in 86.7% of patients, but these were well controlled, indicating that CD19 CAR-T cell therapy is both effective and relatively safe for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of CD19 CAR-T cell therapy for patients with B cell acute lymphoblastic leukemia involving extramedullary relapse. Huang, L., Zhang, M., Wei, G., et al.[2022]

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]

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]

CAR T cell therapy, specifically targeting the CD19 antigen, has shown high response rates in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), indicating its potential as a new treatment option.

Despite its effectiveness, CAR T cell therapy is associated with severe toxicities like cytokine release syndrome and neurotoxicity, which pose challenges for its widespread use and highlight the need for ongoing improvements in the technology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor Therapy in Acute Lymphoblastic Leukemia Clinical Practice. Luskin, MR., DeAngelo, DJ.[2018]

CD19/20/22 CAR T-cells have been developed to effectively target B-lineage acute lymphoblastic leukemia (BL-ALL) that has relapsed with CD19(-) disease, showing efficacy in both laboratory and animal models.

These CAR T-cells maintain their effectiveness against CD19(+) disease while also being able to kill CD19(-) blasts, suggesting they could serve as a new treatment option for patients who do not respond to traditional CD19-targeting therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression. Fousek, K., Watanabe, J., Joseph, SK., et al.[2022]

CAR T cell therapy targeting CD19 has shown remarkable efficacy, achieving complete remission in up to 90% of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), compared to a 30% response rate with traditional chemotherapy.

The therapy involves genetically modifying T cells to express a chimeric antigen receptor, allowing them to effectively target and eliminate cancer cells, although it is important to note that there are unique toxicities associated with this treatment that require careful management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. Davila, ML., Brentjens, RJ.[2023]

References

1. China pubmed.ncbi.nlm.nih.gov

Efficacy and safety of CD19 CAR-T cell therapy for patients with B cell acute lymphoblastic leukemia involving extramedullary relapse. [2022]

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

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

3. 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]

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

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

5. 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]

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

Chimeric Antigen Receptor Therapy in Acute Lymphoblastic Leukemia Clinical Practice. [2018]

7. England pubmed.ncbi.nlm.nih.gov

CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression. [2022]

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

CD19-Targeted CAR T cells as novel cancer immunotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia. [2023]