Dual CAR T Cell Therapy for Acute Lymphoblastic Leukemia

Overseen By Melissa S. Varghese, M.S.

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Stephan Grupp MD PhD

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Hepatitis B, Hepatitis C, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

93 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for children with advanced B cell Acute Lymphoblastic Leukemia (B-ALL), a type of blood cancer. Researchers aim to determine if two CAR T cell therapies, huCART19 and CART22-65s, are safe and effective when used together. The trial consists of two parts: one identifies a safe dose, and the other tests this dose in children who have relapsed or did not respond well to previous treatments. Children with a history of B-ALL who have relapsed or responded poorly to earlier therapies might be suitable candidates for this trial. As a Phase 1, Phase 2 trial, this research seeks to understand how the treatment works and measure its effectiveness in an initial group, offering a chance to be among the first to benefit from this innovative therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot use systemic steroids or immunosuppressants at the time of cell infusion or collection. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that CART22-65s and huCART19 treatments have been tested in previous studies, yielding promising safety results.

For CART22-65s, earlier trials with children and adults with B-cell Acute Lymphoblastic Leukemia (B-ALL) suggested that the treatment is generally well-tolerated. Some patients experienced side effects, mostly manageable. For instance, some had cytokine release syndrome, a common reaction after CAR T-cell therapy, but it was usually mild to moderate.

Regarding huCART19, studies indicate it is safe for patients with B-ALL. Most side effects were mild, though some patients experienced more serious reactions. However, these were generally manageable with proper medical care.

Overall, both CART22-65s and huCART19 have demonstrated a good safety profile in earlier trials. While every treatment carries some risks, the data so far suggests that major issues are uncommon, and side effects are often manageable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CART22-65s and huCART19 because these treatments use a dual CAR T cell therapy approach for Acute Lymphoblastic Leukemia (ALL). Unlike traditional chemotherapy or single CAR T cell therapies like Kymriah (tisagenlecleucel), this dual approach targets two different proteins, CD19 and CD22, on the surface of cancer cells. This dual targeting increases the chances of effectively attacking the cancer cells and potentially lowers the risk of relapse by reducing the chance of the cancer escaping detection. Additionally, this combination therapy aims to address both patients who are naïve to CAR T cell treatments and those who have relapsed after previous CAR T cell therapy, expanding its potential impact.

What evidence suggests that this trial's treatments could be effective for B-ALL?

Research has shown that CART22-65s, a therapy targeting the CD22 protein, holds promise in treating B-cell acute lymphoblastic leukemia (B-ALL). Patients, particularly those whose cancer returned after other treatments, have experienced positive outcomes with this therapy. Studies have also indicated that huCART19, targeting the CD19 protein, effectively treats B-ALL, with many patients showing significant improvement. In this trial, participants will receive both CART22-65s and huCART19 therapies together, potentially enhancing the body's ability to combat leukemia and offering a strong option for those with no other treatments available. Overall, both CART22-65s and huCART19 therapies have demonstrated encouraging results in fighting this disease. ^{1 2 5 6 7}

Who Is on the Research Team?

Regina Myers, MD

Principal Investigator

Children's Hospital of Philadelphia

Are You a Good Fit for This Trial?

This trial is for children and young adults (0-29 years) with advanced B cell Acute Lymphoblastic Leukemia who have either not responded well to previous CAR T cell therapy or have relapsed/refractory ALL/LLy. Participants must show CD19+ and/or CD22+ tumor expression, be in good enough health, agree to birth control if applicable, and cannot be pregnant or nursing.

Inclusion Criteria

Signed informed consent form

My leukemia cells test positive for CD19 or CD22.

My leukemia has returned or is not responding to treatment.

Exclusion Criteria

I do not have any ongoing infections that aren't responding to treatment.

I am currently receiving treatment for Graft Vs. Host Disease.

Active hepatitis B or active hepatitis C

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Finding

Phase 1 will evaluate the safety of co-administration of CART22-65s with huCART19 in patients who experienced a disease relapse after prior CAR T cell therapy.

4 weeks

Multiple visits for dose administration and monitoring

Dose Expansion

Phase 2 dose expansion phase where subjects receive the highest safe dose of CART22-65s and huCART19 cells.

4 weeks

Multiple visits for dose administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of anti-tumor response and CAR T cell persistence.

1 year

Regular follow-up visits for monitoring

What Are the Treatments Tested in This Trial?

Interventions

• CART22-65s
• huCART19

Trial Overview The study tests the safety and effectiveness of two CAR T cell therapies given together: huCART19 and CART22-65s. These are specialized treatments designed to target leukemia cells in patients whose disease has been difficult to treat with standard options.

How Is the Trial Designed?

Group I: Expansion Arm Experimental Treatment 2 Interventions

If at least one dose level of phase 1 is determined to be safe, the phase 2 dose expansion phase of the trial will be opened to enrollment. Subjects will receive the highest dose of CART 22-65s and huCART19 cells that were determined to be safe. 2 cohorts are planned: Cohort A (relapsed/refractory, CAR T cell naïve) \& Cohort B (prior treatment with a prior CAR T cell product).

Group II: Dose Finding Arm Experimental Treatment 2 Interventions

Phase 1 will evaluate the safety of co-administration of CART22-65s with huCART19 in patients who experienced a disease relapse after prior CAR T cell therapy. There is no planned dose escalation but a dose-deescalation will be made based on the incidence of Dose Limiting Toxicities

Who Is Running the Clinical Trial?

Stephan Grupp MD PhD

Lead Sponsor

Trials

5

Recruited

370+

University of Pennsylvania

Collaborator

Trials

2,118

Recruited

45,270,000+

Published Research Related to This Trial

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 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]

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]

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 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]

Two adult patients with relapsed EP300-ZNF384-positive B cell acute lymphoblastic leukemia (B-ALL) achieved second remission after receiving tandem CD19/CD22 CAR T-cell therapy, indicating its potential efficacy for this specific leukemia subtype.

Both patients experienced manageable cytokine release syndrome but did not suffer from neurotoxicity, and they maintained remission for 14 and 13 months after undergoing hematopoietic stem cell transplantation, suggesting a promising treatment pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MRD-Negative Remission Induced in EP300-ZNF384 Positive B-ALL Patients by Tandem CD19/CD22 CAR T-Cell Therapy Bridging to Allogeneic Stem Cell Transplantation. Zhang, XY., Dai, HP., Zhang, L., et al.[2021]

CAR-T cell therapy targeting CD19 has been FDA-approved for treating relapsed and refractory acute lymphoblastic leukemia (ALL) in children and young adults, showing promising efficacy.

Recent trials with CD22-directed CAR-T cells indicate they can also effectively target leukemia, providing a potential alternative to CD19 therapy, although challenges like toxicity management and relapse rates remain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR-T Cell Therapy for Acute Lymphoblastic Leukemia: Transforming the Treatment of Relapsed and Refractory Disease. Pehlivan, KC., Duncan, BB., Lee, DW.[2019]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12007026/

CD22-targeted chimeric antigen receptor-modified T cells for ... This study reports results of parallel phase I trials of a novel CD22 CAR T cell therapy, CART22-65s, in children and adults who experienced ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05674175

Co-administration of CART22-65s and huCART19 for B-ALL This study will evaluate the safety and efficacy of administering two CAR T cell products, huCART19 and CART22-65s, in children with advanced B cell Acute ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S000649711981323X

Clinical Efficacy of Anti-CD22 Chimeric Antigen Receptor T ... Anti-CD19 chimeric antigen receptor T cells (CART19 or CTL019) have shown impressive clinical activity in B-cell acute lymphoblastic leukemia (B-ALL) and are ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40246579/

CD22-targeted chimeric antigen receptor-modified T cells for ... We tested a novel, fully human anti-CD22/4-1BB CAR T-cell construct, CART22-65s, in parallel phase I studies for pediatric and adult B-ALL.

5. jitc.bmj.com jitc.bmj.com/content/13/4/e009048

CD22 CAR-T cells secreting CD19 T-cell engagers ... CD22 CAR-T cells secreting CD19 T-cell engagers show an enhanced control of B-ALL progression compared with CD19/CD22 dual CAR-based therapies.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05674175

Co-administration of CART22-65s and huCART19 for B-ALL This study will evaluate the safety and efficacy of administering two CAR T cell products, huCART19 and CART22-65s, in children with advanced B cell Acute ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02650414

NCT02650414 | CD22 Redirected Autologous T Cells for ALL This is a pilot study to determine the feasibility and safety of a single dose of autologous T cells expressing CD22 chimeric antigen receptors expressing ...