CAR T-Cell Therapy for Leukemia

(PLAT-04 Trial)

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Seattle Children's Hospital

Disqualifiers: CNS dysfunction, Pregnancy, Active infection, others

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

Compensation: Varies

Number of Visits: 2

Duration: 4 weeks

4 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients with relapsed or refractory leukemia often develop resistance to chemotherapy and some patients who relapse following CD19 directed therapy relapse with CD19 negative leukemia. For this reason, the investigators are attempting to use T-cells obtained directly from the patient, which can be genetically modified to express a chimeric antigen receptor (CAR) to CD22, a different protein from CD19, expressed on the surface of the leukemic cell in patients with CD22+ leukemia. The CAR enables the T-cell to recognize and kill the leukemic cell through the recognition of CD22, a protein expressed on the surface of the leukemic cell in patients with CD22+ leukemia. This is a Phase 1 study designed to determine the safety and feasibility of the CAR+ T - cells and the feasibility of making enough to treat patients with CD22+ leukemia.

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 must be free from active GVHD and off immunosuppressive GVHD therapy for 4 weeks, and you should be at least 7 days post your last chemotherapy and systemic corticosteroid administration.

What data supports the effectiveness of this treatment for leukemia?

Research shows that targeting CD22 with CAR T-cells has been effective in treating B-cell malignancies, like acute lymphoblastic leukemia, by specifically attacking cancer cells while sparing most healthy cells. Additionally, combining CD19 and CD22 targeting in CAR T-cell therapy has shown complete responses in some patients with relapsed leukemia, suggesting potential effectiveness for this treatment. ^{1 2 3 4 5}

Is CAR T-cell therapy generally safe for humans?

CAR T-cell therapy, including treatments targeting CD19 and CD22, has shown a favorable safety profile in trials, with manageable side effects. However, some patients may experience significant toxicities like cytokine release syndrome (CRS) and neurotoxicity, which can be severe and require careful management. ^{1 4 6 7 8}

How is CAR T-Cell Therapy for Leukemia different from other treatments?

This treatment is unique because it uses patient-derived T-cells that are genetically modified to specifically target CD22, a protein found on leukemia cells, and also express EGFRt, which helps track and control the therapy. Unlike traditional chemotherapy, this approach directly harnesses the body's immune system to fight cancer. ^{1 9 10 11 12}

Research Team

Corinne Summers, MD

Principal Investigator

Seattle Children's Hospital

Eligibility Criteria

This trial is for children and young adults (12 months to <27 years old) with CD22+ leukemia or lymphoma that's come back or hasn't responded to treatment. They should have recovered from previous treatments, not be pregnant/breastfeeding, free of severe infections, other cancers, primary immunodeficiencies, and able to tolerate apheresis. Participants must agree to long-term follow-up and use effective contraception if applicable.

Inclusion Criteria

Life expectancy of >8 weeks

I am between 18 and 26 years old.

I am between 12 months and 27 years old.

Exclusion Criteria

I do not have any health conditions that would stop me from following the treatment plan.

I cannot undergo apheresis or have a temporary line placed for it.

I am currently suffering from a severe infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive autologous CD22-specific CAR T-cells to assess safety and feasibility

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

Treatment Details

Interventions

• Patient-derived CD22-specific CAR T-cells also expressing an EGFRt

Trial Overview The study tests a new therapy using the patient's own T-cells genetically modified to target CD22 on leukemia/lymphoma cells. It aims to see if these CAR T-cells are safe and can be produced in sufficient amounts for treatment in those who've relapsed after standard therapies or have resistant disease.

Participant Groups

Group I: Autologous CD22-specific CAR T-cells expressing EGFRt Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Seattle Children's Hospital

Lead Sponsor

Trials

319

Recruited

5,232,000+

Findings from Research

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]

CD4 is identified as a promising target for CAR-T cell therapy in treating acute myeloid leukemia (AML), as it is expressed in certain AML subtypes but not on normal hematopoietic stem cells, allowing for targeted treatment.

CD4 redirected CAR-T cells effectively eliminated CD4-expressing AML cells in laboratory settings and demonstrated strong anti-leukemic effects in a mouse model, suggesting potential for clinical application in refractory AML cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells. Salman, H., Pinz, KG., Wada, M., et al.[2020]

In a small trial, T cells modified to target the Wilms tumor antigen 1 were effective in preventing relapse in patients with acute myeloid leukemia after they underwent an allogeneic stem-cell transplant.

This approach highlights the potential of engineered T cell therapies in enhancing post-transplant outcomes for leukemia patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TCR Gene Therapy Improves AML Prognosis. [2020]

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]

A novel T-cell receptor (TCR) targeting the CD22-derived peptide was identified, showing promise for treating B-cell malignancies by effectively recognizing and killing leukemia cells while sparing most healthy cells.

TCR-engineered T-cells demonstrated the ability to selectively target CD22-positive B-cell leukemia, suggesting a complementary approach to existing CAR and antibody therapies, although the presence of CD22 on some non-B-cells may pose challenges for this strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A CD22-reactive TCR from the T-cell allorepertoire for the treatment of acute lymphoblastic leukemia by TCR gene transfer. Jahn, L., Hagedoorn, RS., van der Steen, DM., et al.[2018]

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]

CAR T cells have shown significant clinical effectiveness in treating blood cancers, but their success in solid tumors has been less impressive, highlighting the need for further research in this area.

While CAR T cell therapy can lead to serious side effects like cytokine release syndrome and neurological toxicity, some theoretical risks have not yet been observed in clinical settings, emphasizing the importance of managing known toxicities for safe treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and management in CAR T-cell therapy. Bonifant, CL., Jackson, HJ., Brentjens, RJ., et al.[2023]

Chimeric antigen receptor T-cell (CART) therapy targeting CD22 is effective in inducing remission in 70% of patients with relapsed/refractory acute lymphoblastic leukemia (ALL), but many remissions are short-lived due to reduced CD22 expression on leukemic cells.

Using Bryostatin1 to upregulate CD22 expression significantly enhances CART functionality and persistence, leading to longer-lasting responses in vivo, despite some reduction in IFNγ production by CART.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modulation of Target Antigen Density Improves CAR T-cell Functionality and Persistence. Ramakrishna, S., Highfill, SL., Walsh, Z., et al.[2021]

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]

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]

References

1. 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]

2. Australia pubmed.ncbi.nlm.nih.gov

Preclinical Targeting of Human Acute Myeloid Leukemia Using CD4-specific Chimeric Antigen Receptor (CAR) T Cells and NK Cells. [2020]

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

TCR Gene Therapy Improves AML Prognosis. [2020]

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

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

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

A CD22-reactive TCR from the T-cell allorepertoire for the treatment of acute lymphoblastic leukemia by TCR gene transfer. [2018]

6. United States 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. [2022]

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

Taming the beast: CRS and ICANS after CAR T-cell therapy for ALL. [2022]

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

Toxicity and management in CAR T-cell therapy. [2023]

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

Modulation of Target Antigen Density Improves CAR T-cell Functionality and Persistence. [2021]

10. 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]

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

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

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

Constant attack on T cell lymphomas. [2018]