CAR T-Cell Therapy for Acute Lymphoblastic Leukemia

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Seattle Children's Hospital

Must not be taking: Corticosteroids, Humanized antibodies

Disqualifiers: Philadelphia leukemia, CNS pathology, others

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

Compensation: Varies

Number of Visits: Unknown

6 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients with relapsed leukemia often develop resistance to chemotherapy. For this reason, we are attempting to use a patient's own T cells, which can be genetically modified to expresses a chimeric antigen receptor(CAR). The CAR enables the T cell to recognize and kill the leukemic cells though the recognition of CD19, a protein expressed on the surface of the majority of pediatric ALL. This is a phase I study designed to determine the maximum tolerated dose of the CAR+ T cells and define the toxicity of the treatment. As a secondary aim, we will be looking at the efficacy of the T cells on eradicating the patient's leukemic cells.

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 cannot have taken systemic corticosteroids within 7 days of enrollment.

What data supports the effectiveness of the treatment Autologous CD19 CAR+ EGFTt + T cells for Acute Lymphoblastic Leukemia?

Research shows that CD19 CAR T-cell therapy has led to high remission rates in patients with relapsed and refractory acute lymphoblastic leukemia, with a 90% remission rate reported in one study. This suggests that the treatment can be effective in achieving remission in difficult cases of leukemia. ^{1 2 3 4 5}

What safety data exists for CAR T-Cell Therapy in humans?

CAR T-Cell Therapy, including CD19 CAR T cells, has shown promise in treating leukemia but can cause side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). These side effects are usually manageable with treatments like anti-cytokine drugs and steroids. ^{6 7 8 9 10}

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

This treatment is unique because it uses the patient's own T cells, which are modified to specifically target and attack leukemia cells by recognizing a marker called CD19 on their surface. Unlike traditional chemotherapy, this approach allows the modified T cells to expand and continue fighting cancer cells over time, although it can cause severe side effects like cytokine release syndrome and neurotoxicity. ^{1 2 8 11 12}

Research Team

Colleen Annesley, MD

Principal Investigator

Seattle Children's Hospital

Eligibility Criteria

This trial is for children and young adults aged 1-26 with CD19+ Leukemia that's relapsed multiple times. Participants must have a certain level of physical fitness, adequate organ function, no severe infections or other health conditions that could interfere with the treatment, and not be pregnant. They should also agree to long-term follow-up.

Inclusion Criteria

My lymphocyte count is high enough for the trial.

My leukemia has returned and shows specific markers after initial treatment.

My leukemia has returned at least twice and tests positive for CD19.

Exclusion Criteria

I haven't taken any corticosteroids in the last week.

I have a primary immunodeficiency or bone marrow failure.

I do not have any major brain-related health issues.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Cell Generation

T cells are isolated, transduced with a lentivirus to express the CD19 CAR, and expanded in culture

3 weeks

Lymphodepletion and Treatment

Participants receive 2 days of cyclophosphamide followed by an infusion of CAR+ T cells

1 week

Intensive Follow-up

Participants are intensely followed with serial blood testing and disease status re-evaluation

6 weeks

Long-term Follow-up

Participants are followed annually for 15 years to monitor long-term health and potential new cancers

15 years

Treatment Details

Interventions

• Autologous CD19 CAR+ EGFTt + T cells

Trial Overview The study tests genetically modified T cells designed to attack leukemia by recognizing a protein called CD19 on cancer cells. It aims to find the highest safe dose of these CAR+ T cells and assess their toxicity as well as effectiveness in treating leukemia.

Participant Groups

Group I: CAR+ T cells Experimental Treatment 1 Intervention

Subjects will receive two days of cyclophosphamide for a total of 3g/m\^2 followed several days later by a single dose of Autologous CD19 CAR+ EGFTt + T cells

Who Is Running the Clinical Trial?

Seattle Children's Hospital

Lead Sponsor

Trials

319

Recruited

5,232,000+

Findings from Research

An 11-year-old girl with relapsed acute B lymphoblastic leukemia (B-ALL) was treated with fourth generation CD19 CAR-T therapy, which was found to be effective and safe, resulting in a negative minimal residual disease after treatment.

Despite initial success and 10 months of disease-free survival, the patient ultimately relapsed due to increasing TEL-AML1 gene copies, highlighting the need for ongoing monitoring and potential further interventions in CAR-T therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chimeric antigen receptors T cells in treatment of a relapsed pediatric acute lymphoblastic leukemia, relapse after allogenetic hematopoietic stem cell transplantation: case report and review of literature review]. Zuo, Y., Wang, J., Lu, A., et al.[2020]

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]

The study found that high levels of leukemia blast contamination in the starting material did not negatively impact the manufacturing of CAR T-cells or their ability to expand, suggesting that CAR T-cell therapy can be safely produced even from contaminated samples.

Using a specific CAR design with a short linker (CAR.CD19 SL) enhances the ability of CAR T-cells to target and kill CD19+ leukemia cells, providing a potential safety advantage in preventing leukemic relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts. Quintarelli, C., Guercio, M., Manni, S., et al.[2022]

In a phase 1b/2 study involving 21 patients with relapsed and refractory acute lymphoblastic leukemia (R/R ALL), autologous CD19 CAR T cell therapy achieved a remarkable remission rate of 90%, including successful treatment of extramedullary leukemic sites.

While 16 patients experienced cytokine release syndrome and 11 had neurotoxicity, there were no toxic deaths, indicating that the treatment is relatively safe despite these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia. Jacoby, E., Bielorai, B., Avigdor, A., et al.[2019]

A 71-year-old woman with relapsed and refractory acute lymphoblastic leukemia (ALL) achieved undetectable minimal residual disease after receiving haplo-identical donor-derived CD19 CAR-T cells combined with mobilized peripheral blood stem cells, indicating potential efficacy in treating elderly patients.

While the treatment led to full donor cell engraftment, it also caused transient cytokine release and mild fever, along with reversible increases in liver enzymes, highlighting the need for caution regarding complications from donor cell infusions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Co-infusion of haplo-identical CD19-chimeric antigen receptor T cells and stem cells achieved full donor engraftment in refractory acute lymphoblastic leukemia. Cai, B., Guo, M., Wang, Y., et al.[2018]

Adoptive cellular therapy using CD19 CAR T cells has shown remarkable efficacy in achieving remission in 67-90% of patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), indicating a promising treatment option for this high-risk group.

While CD19 CAR T-cell therapy can lead to significant toxicities such as cytokine release syndrome and neurologic dysfunction, these effects are generally manageable with supportive care, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL). Tasian, SK., Gardner, RA.[2020]

CD19 CAR T-cell therapy has shown a high complete remission rate in pediatric acute lymphoblastic leukemia, highlighting its efficacy as a treatment for this type of cancer.

Despite its effectiveness, CD19 CAR T-cell therapy is associated with significant adverse reactions and an increased risk of cancer recurrence, necessitating further research into mechanisms of recurrence and strategies to mitigate these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cluster of differentiation 19 chimeric antigen receptor T-cell therapy in pediatric acute lymphoblastic leukemia. Fu, Z., Zhou, J., Chen, R., et al.[2020]

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]

CD19CAR-T cell therapy is effective in treating relapsed and refractory B-lineage acute lymphoblastic leukemia, with four out of five patients achieving complete remission and minimal residual disease negativity.

The therapy can be safely administered with real-time monitoring of a 6-cytokine pattern, allowing for effective management of side effects like cytokine release syndrome and neurotoxicity using tocilizumab and steroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T cell therapy can be administered safely under the real-time monitoring of Th1/Th2 cytokine pattern using the cytometric bead array technology for relapsed and refractory acute lymphoblastic leukemia in children. Shen, D., Song, H., Xu, X., et al.[2021]

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]

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]

References

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

[Chimeric antigen receptors T cells in treatment of a relapsed pediatric acute lymphoblastic leukemia, relapse after allogenetic hematopoietic stem cell transplantation: case report and review of literature review]. [2020]

2. 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]

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

Strategy to prevent epitope masking in CAR.CD19+ B-cell leukemia blasts. [2022]

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

Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia. [2019]

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

Co-infusion of haplo-identical CD19-chimeric antigen receptor T cells and stem cells achieved full donor engraftment in refractory acute lymphoblastic leukemia. [2018]

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

CD19-redirected chimeric antigen receptor-modified T cells: a promising immunotherapy for children and adults with B-cell acute lymphoblastic leukemia (ALL). [2020]

7. Greece pubmed.ncbi.nlm.nih.gov

Cluster of differentiation 19 chimeric antigen receptor T-cell therapy in pediatric acute lymphoblastic leukemia. [2020]

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

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

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

Cytokine Release Syndrome: Inpatient Care for Side Effects of CAR T-Cell Therapy . [2018]

10. England pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptor T cell therapy can be administered safely under the real-time monitoring of Th1/Th2 cytokine pattern using the cytometric bead array technology for relapsed and refractory acute lymphoblastic leukemia in children. [2021]

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

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

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

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