Cellular Immunotherapy for Acute Lymphoblastic Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

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

Compensation: Varies

Number of Visits: 24

71 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of cellular immunotherapy in treating patients with high-risk acute lymphoblastic leukemia. Placing a modified gene into white blood cells may help the body build an immune response to kill cancer cells.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but it does mention that you need to be off immunosuppressant medications for at least 2 weeks before a certain procedure, with some exceptions for steroids and tyrosine kinase inhibitors. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the treatment CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytes for acute lymphoblastic leukemia?

Research shows that CAR T-cell therapies targeting CD19 have been effective in treating acute lymphoblastic leukemia, with high remission rates reported. Additionally, T-cells with central memory (Tcm) and stem cell-like memory (Tscm) phenotypes are known to promote sustained proliferation and persistence, which are important for treatment success. ^{1 2 3 4 5}

Is CD19 CAR T-cell therapy safe for humans?

CD19 CAR T-cell therapy has shown some safety concerns, including severe but generally manageable side effects like cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). These side effects are usually temporary and can be treated with supportive care. ^{6 7 8 9 10}

How is the treatment with CD19CAR-CD28-CD3zeta-EGFRt-expressing T-lymphocytes different from other treatments for acute lymphoblastic leukemia?

This treatment is unique because it uses genetically engineered T-cells that are designed to specifically target and attack leukemia cells, potentially offering a more precise and effective approach compared to traditional chemotherapy. It also incorporates a novel combination of components (CD19CAR-CD28-CD3zeta-EGFRt) to enhance the T-cells' ability to persist and function, which may improve outcomes for patients with relapsed or refractory acute lymphoblastic leukemia. ^{1 3 8 11 12}

Research Team

Ibrahim Aldoss, MD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for patients with high-risk acute lymphoblastic leukemia who have had a relapse or still have disease after treatment. They must be in good physical condition, not need oxygen support, and have normal organ function. Pregnant women and those with active infections or other cancers are excluded.

Inclusion Criteria

I have a small amount of cancer cells left after my first treatment.

Patients with CNS involvement by leukemia (CNS2 and CNS3) after discussions with the study team

I am mostly able to care for myself and carry out daily activities.

Exclusion Criteria

I am not currently on any experimental treatments or undergoing chemotherapy or radiation.

I have a disorder that affects my lymph cells.

I do not have any uncontrolled illnesses or conditions that would limit my participation.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Patients receive a lymphodepleting regimen 3-14 days before T-cell infusion

1-2 weeks

T-cell Infusion

Patients receive CD19CAR-CD28-CD3zeta-EGFRt-expressing T cells IV over 15 minutes on day 0

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 15 years

24 hours post-infusion, weekly for 1 month, monthly for 1 year, then yearly

Treatment Details

Interventions

• CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T-lymphocytes
• CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/mem-enriched T-lymphocytes

Trial Overview The trial tests cellular immunotherapy by modifying white blood cells to fight cancer. It aims to determine the best dose and side effects of this therapy using T-lymphocytes engineered to target leukemia cells.

Participant Groups

Group I: Arm I (cellular immunotherapy closed to accrual January 2019) Experimental Treatment 2 Interventions

Patients receive lymphodepleting regimen per treating physician's discretion 3-14 days before the T-cell infusion. Patients receive CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T cells IV over 15 minutes on day 0. Patients who have evidence of disease, whose tumor(s) continue to express the appropriate antigen target may receive an optional second infusion of CD19CAR-CD28-CD3zeta-EGFRt-expressing Tcm-enriched T cells after 28 days.

Group II: Arm II (cellular immunotherapy) Active Control 2 Interventions

Patients receive lymphodepleting regimen per treating physician's discretion 3-14 days before the T-cell infusion. Patients receive CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/nem-enriched T cells IV over 15 minutes on day 0. Patients who have evidence of disease, whose tumor(s) continue to express the appropriate antigen target may receive an optional second infusion of CD19CAR-CD28-CD3zeta-EGFRt-expressing Tn/nem-enriched T cells after 28 days.

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has become a significant advancement in treating relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), with two such therapies approved by regulatory agencies.

Despite the success of CD19-targeting CAR T-cells, some patients still experience relapses, highlighting the need for ongoing research into resistance mechanisms and potential strategies to overcome them.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia. Saleh, K., Pasquier, F., Bigenwald, C., et al.[2023]

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]

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]

In a phase I trial involving 12 younger patients with relapsed or refractory B-cell acute lymphoblastic leukemia, the use of chimeric antigen receptor T cells targeting CD19 and CD22 showed manageable toxicity levels.

Out of the 12 patients, 5 achieved complete responses, indicating promising efficacy of this treatment approach in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting CD19-CD22 Aids Younger Patients with ALL. [2021]

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]

T-cell acute lymphoblastic leukemia (T-ALL) remains difficult to treat, especially in relapsed or resistant cases, due to limited novel therapeutic options and challenges like shared surface targets between normal and cancerous T-cells.

Recent advancements in immunotherapy, including monoclonal antibodies, bispecific T-cell engagers (BTCEs), and CAR T-cells, show promising results and are progressing through clinical trials, offering hope for improved treatment strategies for T-ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging scenario of immunotherapy for T-cell Acute Lymphoblastic Leukemia: advances, challenges and future perspectives. Caracciolo, D., Mancuso, A., Polerà, N., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Vaccination to improve the persistence of CD19CAR gene-modified T cells in relapsed pediatric acute lymphoblastic leukemia. [2022]

2. China pubmed.ncbi.nlm.nih.gov

Advances in the development of chimeric antigen receptor-T-cell therapy in B-cell acute lymphoblastic leukemia. [2021]

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

Antibody and cellular immunotherapies for acute lymphoblastic leukemia in adults. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

Induction of a central memory and stem cell memory phenotype in functionally active CD4+ and CD8+ CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19+ acute lymphoblastic leukemia. [2019]

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

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

6. Switzerland pubmed.ncbi.nlm.nih.gov

CAR T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia. [2023]

7. 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]

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

Targeting CD19-CD22 Aids Younger Patients with ALL. [2021]

10. Greece pubmed.ncbi.nlm.nih.gov

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

11. England pubmed.ncbi.nlm.nih.gov

The emerging scenario of immunotherapy for T-cell Acute Lymphoblastic Leukemia: advances, challenges and future perspectives. [2023]

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

Redirecting T cells with Chimeric Antigen Receptor (CAR) for the treatment of childhood acute lymphoblastic leukemia. [2018]