T-APCs after CAR T Therapy for Leukemia

Overseen By Colleen Annesley, MD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Seattle Children's Hospital

Must not be taking: Immunosuppressives

Disqualifiers: CNS dysfunction, Active malignancy, GVHD, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a method to enhance CD19 CAR-T cell therapy for individuals whose leukemia has returned or resisted other treatments. Researchers are testing whether a follow-up treatment with T-APCs, which boosts CAR-T cells, can extend their presence in the body and prevent leukemia recurrence. Participants will be grouped based on their response to initial CAR-T treatment and may receive additional T-APC treatments as needed. The trial seeks participants with recurrent or difficult-to-treat CD19+ leukemia who are in good overall health. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on immunosuppressive therapy for GVHD (graft-versus-host disease), you must stop it at least 4 weeks before enrolling.

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

Research has shown that CD19 CAR-T cell therapy has generally been well-tolerated in past studies. For example, patients with certain types of leukemia managed nerve damage effectively. This suggests the treatment is relatively safe, although some side effects can occur.

The current trial tests whether adding T-APCs (a type of cell that helps the immune system) after CAR-T therapy can extend the treatment's duration in the body. Researchers focus on the safety and practicality of this approach. They continue to learn how people respond to T-APCs but remain hopeful based on earlier results with CAR-T cells alone.

In summary, while some risks are known, the treatment has shown promise in being manageable for patients so far. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they involve CD19-targeting CAR T cells, which represent a cutting-edge approach to fighting leukemia. Unlike traditional chemotherapy or radiation, CAR T cell therapy is personalized, as it uses the patient's own immune cells that are genetically modified to attack cancer cells. This method offers the potential for a more precise and effective treatment by directly targeting the cancerous cells while minimizing damage to healthy cells. Additionally, the use of T-APC treatments in this trial aims to enhance the longevity and effectiveness of the CAR T cells, which could lead to improved outcomes and reduce the chances of relapse.

What evidence suggests that this trial's treatments could be effective for leukemia?

Research has shown that CD19 CAR-T cell therapy yields promising results for treating leukemia. In earlier studies, 89% of patients achieved complete remission, with no detectable cancer after treatment. The rate of remaining leukemia-free was 71% at both one and two years post-treatment. In this trial, participants will receive CD19 CAR-T cells, and researchers are examining T cell antigen presenting cells (T-APCs) to determine if they can extend the presence of CAR-T cells in the body. This could reduce the likelihood of leukemia returning. T-APCs may reactivate and increase the number of CAR-T cells, enhancing their effectiveness over time. Participants in different cohorts may receive T-APC treatments based on specific criteria related to their response to CAR-T cell therapy. ^{1 2 3 6 7}

Who Is on the Research Team?

Colleen Annesley, MD

Principal Investigator

Seattle Children's Hospital

Are You a Good Fit for This Trial?

This trial is for people with CD19+ leukemia that came back or didn't respond to treatment, but are now in remission after CAR-T cell therapy. They must have good kidney, liver, heart, and lung function; a decent number of lymphocytes; no HIV or hepatitis B/C; be able to handle apheresis (a procedure to collect blood cells); and not have serious brain issues, other active cancers, or recent treatments for graft-versus-host disease.

Inclusion Criteria

I am generally healthy and active.

My kidney, liver, heart, and lung functions are all good.

HIV negative

Exclusion Criteria

I have significant brain function issues.

I have an active cancer that is not CD19 positive.

I have active GVHD or have been on GVHD treatment in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive CD19-targeting CAR T cells followed by up to 6 T-APC treatments

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• CD19 CAR-T cells
• T-APCs

Trial Overview The study is testing if giving T-cell Antigen Presenting Cells (T-APCs) after CAR-T cell therapy can make the CAR-T cells last longer and prevent leukemia from coming back. Patients who've had success with initial CAR-T treatment will receive these additional T-APCs at set times.

How Is the Trial Designed?

Group I: Cohort D Experimental Treatment 1 Intervention

Participants will receive CD19-targeting CAR T cells. Participants who do not meet assignment rules for Cohorts A, B, or C will be followed after CAR T cell infusion in Cohort D.

Group II: Cohort C Experimental Treatment 1 Intervention

Participants will receive CD19-targeting CAR T cells. Participants for whom laboratory testing shows loss of CAR T cells within 6 months will be assigned to Cohort C. They will receive another CAR T cell infusion followed by up to 6 T-APC treatments.

Group III: Cohort B Experimental Treatment 1 Intervention

Participants will receive CD19-targeting CAR T cells. Participants for whom laboratory testing on Study Day 14 indicates they are at risk for early loss of CAR T cells will be assigned to Cohort B to receive up to 6 T-APC treatments. If laboratory testing prior to planned T-APC treatment indicates loss of CAR-T cells, participants may move to Cohort C.

Group IV: Cohort A Experimental Treatment 1 Intervention

Participants will receive CD19-targeting CAR T cells. Participants who have a total CD19 antigen load in bone marrow of \<15% will be assigned to Cohort A, to receive up to 6 T-APC treatments.

Who Is Running the Clinical Trial?

Seattle Children's Hospital

Lead Sponsor

Trials

319

Recruited

5,232,000+

Published Research Related to This Trial

The study introduces a novel Fab-based adapter CAR (AdCAR) T-cell platform that allows for flexible targeting of acute myeloid leukemia (AML) cells, demonstrating effective cytotoxicity against AML cell lines and primary AML cells using various adapter molecules.

The AdCAR platform also shows promise in overcoming T-cell exhaustion by incorporating treatment-free intervals, which could enhance the effectiveness of CAR T-cell therapy in AML patients who face challenges like target antigen heterogeneity and T-cell dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adapter CAR T cells to counteract T-cell exhaustion and enable flexible targeting in AML. Nixdorf, D., Sponheimer, M., Berghammer, D., et al.[2023]

In a study of 43 patients with CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) who relapsed after an allotransplant, 79% achieved complete remission after receiving allogeneic anti-CD19 CAR-T cells, indicating high efficacy of this treatment.

While the therapy was effective, it was associated with a high incidence of cytokine release syndrome (CRS) in 88% of patients, highlighting the need for careful monitoring and management of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Donor-derived CD19 CAR-T cell therapy of relapse of CD19-positive B-ALL post allotransplant. Zhang, C., Wang, XQ., Zhang, RL., et al.[2021]

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 has shown promising results in treating acute lymphoblastic leukemia, with high rates of complete and prolonged clinical responses, indicating its potential as a powerful treatment option.

CAR T cells work by specifically targeting tumor-associated antigens, acting as a 'living drug' that can provide long-term anti-tumor memory, although there are specific but manageable adverse events associated with the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive immunotherapy for acute leukemia: New insights in chimeric antigen receptors. Heiblig, M., Elhamri, M., Michallet, M., et al.[2020]

CD7-CAR T cells, which are modified to avoid fratricide by using naturally occurring CD7- T cells, showed strong antitumor activity against T-cell acute lymphoblastic leukemia (T-ALL) in both laboratory and mouse models.

In a comparison of CD19-CAR T cells, those derived from CD7- T cells demonstrated enhanced antitumor effects, and a higher presence of CD7-low expressing T cells was associated with better patient responses in a clinical study, suggesting a promising avenue for immunotherapy in hematological malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering naturally occurring CD7- T cells for the immunotherapy of hematological malignancies. Freiwan, A., Zoine, JT., Crawford, JC., et al.[2023]

CAR T-cell therapy has the potential to improve outcomes for patients with acute myeloid leukemia (AML) by specifically targeting leukemia cells, but there are significant challenges to its effectiveness and safety.

Strategies being explored to enhance CAR T-cell therapy in AML include targeting specific leukemia antigens to reduce side effects, using checkpoint inhibitors to counteract immune suppression caused by leukemia, and developing allogenic CAR T cells to make the treatment more accessible to patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospect of CAR T-cell therapy in acute myeloid leukemia. Badar, T., Manna, A., Gadd, ME., et al.[2022]

CD19+ CAR T-cells have shown high effectiveness against various cancers, but their complete risk profile, including complications, was not fully understood during initial clinical trials.

Emerging evidence from post-approval studies reveals significant complications associated with CD19+ CAR T-cell therapy, such as cytokine release syndrome and neurotoxicity, indicating that these therapies can affect multiple organ systems and may lead to long-term health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complications after CD19+ CAR T-Cell Therapy. Penack, O., Koenecke, C.[2020]

CD19-specific CAR T-cell therapy shows high initial remission rates (over 80%) in pediatric patients with relapsed or refractory B-ALL, but only 40% to 50% achieve durable remission.

The review discusses the potential benefits of consolidative hematopoietic cell transplantation for patients who achieve a complete response after CAR T-cell therapy, as well as strategies to enhance the effectiveness and longevity of CAR T cells in preventing relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preventing relapse after CD19 CAR T-cell therapy for pediatric ALL: the role of transplant and enhanced CAR T cells. Talleur, AC., Naik, S., Gottschalk, S.[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]

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]

In a study of 35 patients with refractory acute lymphoblastic leukemia (ALL), CAR-T cell therapy demonstrated a high total effective rate of 91.43%, with 68.57% achieving complete response after one month of treatment.

The therapy was associated with significant changes in immune cell populations, including a decrease in regulatory T cells and an increase in natural killer cells, while side effects were generally mild and manageable, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of CAR-T Cell Therapy on Immune Cells and Related Toxic Side Effect Analysis in Patients with Refractory Acute Lymphoblastic Leukemia. Li, L., Gao, J., Sun, Z., et al.[2023]

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CAR-T cell therapy for cancer: current challenges and ... This review begins with a comprehensive overview of CAR-T cell therapy for cancer, covering the structure of CAR-T cells and the history of their clinical ...