CAR T-cell Therapy for Acute Lymphoblastic Leukemia

Overseen By Vanessa Fabrizio, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Colorado, Denver

Disqualifiers: CNS leukemia, Severe organ dysfunction, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

26 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will evaluate the safety and tolerability of administering a novel bispecific CD19/CD22-directed CAR T cell product (CD19x22) for the treatment of relapsed or refractory pediatric B-ALL.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of this treatment?

Research shows that targeting both CD19 and CD22 with CAR T-cell therapy can help patients with acute lymphoblastic leukemia (ALL) who have relapsed or are resistant to other treatments. In one study, five out of twelve younger patients had complete responses, and another study found that 73% of patients achieved complete remission with CD22-targeted therapy, even when resistant to CD19-targeted therapy. ^{1 2 3 4 5}

Is CD19/CD22 CAR T-cell therapy safe for humans?

CD19/CD22 CAR T-cell therapy has been studied in patients with acute lymphoblastic leukemia and other B-cell cancers, showing manageable side effects. While some patients experience severe reactions like cytokine release syndrome (a severe immune response) and ICANS (a type of brain-related side effect), these are rare. Overall, the therapy is considered generally safe, but long-term safety data is still needed. ^{1 2 5 6 7}

How is the CD19x22 CAR T-cell treatment different from other treatments for acute lymphoblastic leukemia?

The CD19x22 CAR T-cell treatment is unique because it targets both CD19 and CD22 proteins on leukemia cells, which helps prevent the cancer from escaping treatment by losing one of these targets, a common issue with single-target therapies. ^{1 4 5 8 9}

Research Team

Vanessa Fabrizio, MD

Principal Investigator

University of Colorado, Denver

Eligibility Criteria

This trial is for children with a type of blood cancer called B-ALL that has come back or hasn't responded to treatment. Participants should meet specific health conditions, but the exact criteria aren't provided here.

Inclusion Criteria

Provision of signed consent form from appropriate party

Willingness to comply with study procedures and long-term follow-up protocol

I have had B-cell acute lymphoblastic leukemia with a specific type of relapse.

Exclusion Criteria

I have HIV or active Hepatitis B/C.

I am a woman who has gone through puberty and have a pregnancy-related condition.

I have leukemia in my brain that is not under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Participants receive lymphodepleting chemotherapy prior to CAR T cell infusion

1 week

Treatment

Participants receive CD19x22 CAR T cell therapy with dose escalation based on body weight

4 weeks

Weekly visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Treatment Details

Interventions

• CD19x22 Chimeric Antigen Receptor T-cell Therapy

Trial Overview The study tests a new therapy where T-cells (a type of immune cell) are engineered to target and kill leukemia cells by recognizing two proteins, CD19 and CD22, on their surface.

Participant Groups

Group I: Lymphodepleting chemotherapy with CD19x22 CAR T cohort Experimental Treatment 1 Intervention

A single participant will receive each dose and will be evaluated for at least the DLT period of 28 days post-infusion before the next participant receives a dose. CD19x22 CAR T will be dosed based on recipient body weight. Phase I Dose Level (DL) CD19x22 CAR T dose -1 1 x 10(to the 5th) Viable CD3+ CAR+ cells/kg of cell dosing weight 1. (starting dose) 3 x 10(to the 5th) Viable CD3+ CAR+ cells/kg of cell dosing weight 2. 1 x 10(to the 6th) Viable CD3+ CAR+ cells/kg of cell dosing weight 3. 3 x 10(to the 6th) Viable CD3+ CAR+ cells/kg of cell dosing weight

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

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 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]

In a study involving 58 children and young adults with relapsed or refractory B-cell malignancies, CD22-targeted CAR T cells achieved a complete remission rate of 70%, demonstrating significant efficacy as an alternative treatment for patients who did not respond to CD19-targeted therapies.

The treatment was generally safe, with most side effects being mild to moderate, although cytokine release syndrome occurred in 86.2% of participants, indicating the need for careful monitoring and potential toxicity management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD4/CD8 T-Cell Selection Affects Chimeric Antigen Receptor (CAR) T-Cell Potency and Toxicity: Updated Results From a Phase I Anti-CD22 CAR T-Cell Trial. Shah, NN., Highfill, SL., Shalabi, H., et al.[2021]

In a phase 1 trial involving 21 patients, including 17 who had previously undergone CD19-targeted therapy, a new CD22-targeted CAR T cell therapy showed a complete remission rate of 73% in patients receiving sufficient doses (≥1 × 10^6 CD22-CAR T cells per kg).

The study highlights that while CD22-CAR T cells are effective against B-ALL, relapses were linked to lower CD22 site density, indicating that the density of target antigens plays a crucial role in the effectiveness of CAR T cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Fry, TJ., Shah, NN., Orentas, RJ., et al.[2022]

A patient with relapsed and refractory B cell acute lymphoblastic leukemia (B-ALL) achieved over 14 months of minimal residual disease-negative remission after receiving CAR-T cell therapy targeting both CD19 and CD22.

This case suggests that dual-targeting CAR-T cell therapy may enhance the durability of remission in B-ALL patients, potentially addressing issues of antigen escape seen with single-target therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical CD19/CD22 bispecific CAR-T cells induced MRD-negative remission in a patient with relapsed and refractory adult B-ALL after haploidentical hematopoietic stem cell transplantation. Jia, H., Wang, Z., Wang, Y., et al.[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]

CD22-targeting CAR T-cell therapies show high complete response rates, with 68% in acute lymphoblastic leukemia (ALL) and 64% in non-Hodgkin's lymphoma (NHL), indicating their efficacy in treating these malignancies.

The incidence of severe side effects, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), is low, suggesting that these therapies are relatively safe, especially with dual-targeting CAR T-cells not increasing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review and meta-analysis of CD22 CAR T-cells alone or in combination with CD19 CAR T-cells. Fergusson, NJ., Adeel, K., Kekre, N., et al.[2023]

CAR T cell therapy, particularly targeting CD19, has shown promising results in treating pediatric patients with relapsed and refractory B cell acute lymphoblastic leukemia (ALL), offering a new hope for those with high-risk disease.

The review highlights the need for exploring additional therapeutic targets for other high-risk leukemia types, such as T cell ALL, acute myeloid leukemia (AML), and infant ALL, to improve treatment outcomes in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beyond CD19: Opportunities for Future Development of Targeted Immunotherapy in Pediatric Relapsed-Refractory Acute Leukemia. Shalabi, H., Angiolillo, A., Fry, TJ.[2022]

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. 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

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

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

CD4/CD8 T-Cell Selection Affects Chimeric Antigen Receptor (CAR) T-Cell Potency and Toxicity: Updated Results From a Phase I Anti-CD22 CAR T-Cell Trial. [2021]

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

CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. [2022]

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

Haploidentical CD19/CD22 bispecific CAR-T cells induced MRD-negative remission in a patient with relapsed and refractory adult B-ALL after haploidentical hematopoietic stem cell transplantation. [2020]

6. Greece pubmed.ncbi.nlm.nih.gov

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

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

A systematic review and meta-analysis of CD22 CAR T-cells alone or in combination with CD19 CAR T-cells. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Beyond CD19: Opportunities for Future Development of Targeted Immunotherapy in Pediatric Relapsed-Refractory Acute Leukemia. [2022]

9. England pubmed.ncbi.nlm.nih.gov

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