CAR T-Cell Therapy for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Autoimmune disease, Active infection, others

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

Compensation: Varies

Number of Visits: 2

Duration: 1 day

27 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called CAR T-cell therapy to combat acute myeloid leukemia (AML) that has either returned after initial treatment or never responded. The main goal is to determine the therapy's safety, potential side effects, and optimal dosage. CAR T-cell therapy involves modifying a person's immune cells in a lab to better target and attack cancer cells. The trial seeks participants with active AML that tests positive for a specific marker (CD33+) and who have faced challenges with previous treatments. As a Phase 1 trial, this research aims to understand 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 requires stopping certain medications, such as systemic steroids and immunosuppressants, 28 days before joining. If you're on antifungal treatment, you must stop it 8 weeks before enrolling, but antifungal prevention is allowed.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that anti-CD33 CAR T-cell therapy might help treat acute myeloid leukemia (AML). In earlier studies, these specially modified T-cells found and attacked cancer cells, but some safety concerns arose. For instance, patients experienced a decrease in normal cells that also have CD33, leading to side effects.

Additionally, early research on similar treatments, like CD33 CAR-NK cells, found a balance between effectiveness and safety. These treatments reduced severe side effects while still targeting cancer cells. The current trial is in its early stages, focusing on understanding the treatment’s safety and determining the best dose.

So far, information suggests that anti-CD33 CAR T-cell therapy might be safe, but it is too early to confirm. Participants will be closely monitored to learn more about the treatment's effects and potential side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about anti-CD33 CAR T-cell therapy for acute myeloid leukemia (AML) because it offers a novel approach by genetically modifying a patient's own immune cells to specifically target and destroy cancer cells expressing the CD33 protein. Unlike traditional chemotherapy or targeted therapies that can harm both cancerous and healthy cells, this treatment is designed to hone in on and eliminate just the cancer cells, potentially reducing side effects. Additionally, this personalized therapy could provide an option for patients who haven't responded well to existing treatments, offering hope for improved outcomes.

What evidence suggests that anti-CD33 CAR T-cells might be an effective treatment for acute myeloid leukemia?

Research shows that anti-CD33 CAR T-cell therapy, which participants in this trial will receive, may help treat acute myeloid leukemia (AML). In some studies, patients achieved complete remission, meaning their cancer was greatly reduced, but their blood counts hadn't fully recovered yet. This is known as CRi. The therapy uses modified T-cells to find and attack AML cells with a marker called CD33, common in this type of leukemia. While some patients experienced side effects, the treatment effectively reduced cancer cells. Overall, evidence suggests this therapy could offer new hope for people with difficult-to-treat AML. ^{1 3 4 5 6}

Who Is on the Research Team?

Karamjeet Sandhu, M.D.

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

Adults with acute myeloid leukemia (AML) that has returned or is unresponsive to treatment, who have a life expectancy of at least 16 weeks and are in relatively good health as indicated by certain organ function tests. Participants must not be pregnant, agree to use birth control, and have a potential stem cell donor. Those with active autoimmune diseases, other cancers, significant heart issues within the past 6 months, or infections like HIV or hepatitis are excluded.

Inclusion Criteria

My cancer has been confirmed to be CD33 positive within the last 3 months.

Participants with Gilbert syndrome may be included if their total bilirubin is =< 3.0

Assent, when appropriate, will be obtained per institutional guidelines

Exclusion Criteria

Any other condition that would, in the Investigator's judgment, contraindicate the subject's participation in the clinical study due to safety concerns with clinical study procedures

My heart rhythm problem is not stable, even with medication, and I'm about to undergo leukapheresis.

I am not pregnant or breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion

Patients undergo lymphodepletion therapy 3-5 days prior to CAR T cell infusion

1 week

1 visit (in-person)

Treatment

Patients receive anti-CD33 CAR T-cells intravenously on day 0

1 day

1 visit (in-person)

Optional Re-treatment

Patients with persistent CD33+ AML may optionally receive additional anti-CD33 CAR T-cells if eligible

Varies

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 15 years

What Are the Treatments Tested in This Trial?

Interventions

• Anti-CD33 CAR T-cells
• Lymphodepletion Therapy

Trial Overview The trial is testing anti-CD33 CAR T-cell therapy for AML patients whose cancer has either come back after treatment or hasn't responded at all. The therapy involves modifying immune cells to target cancer cells more effectively. It's in phase I to determine safety and optimal dosing.

How Is the Trial Designed?

Group I: Treatment (anti-CD33 CAR T-cells) Experimental Treatment 2 Interventions

Patients undergo lymphodepletion therapy 3-5 days prior to CAR T cell infusion and receive anti-CD33 CAR T-cells IV on day 0. Patients with persistent CD33+ AML who are \> 28 days past the initial CAR T infusion, have additional product available and did not experience a dose-limiting toxicity, may optionally receive anti-CD33 CAR T-cells IV.

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+

Published Research Related to This Trial

A novel second-generation chimeric antigen receptor (CAR) targeting CD33 has been developed, showing effectiveness in redirecting T cells to kill acute myeloid leukemia (AML) cells, which express CD33 in about 90% of cases.

In pre-clinical studies, this CAR therapy demonstrated significant anti-leukemia effects both in vitro and in vivo, effectively preventing leukemia development and delaying disease progression in mice, supporting its potential as a clinical treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia. O'Hear, C., Heiber, JF., Schubert, I., et al.[2021]

CAR T-cell therapy shows promise in improving outcomes for patients with acute myeloid leukemia (AML), a condition with historically poor prognosis.

A significant challenge for the effectiveness of CAR T-cell therapy in AML is the identification of specific target antigens on leukemia cells, as well as the risk of immune escape due to changes in these antigens and a suppressive tumor environment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current challenges for CAR T-cell therapy of acute myeloid leukemia. Sauer, T., Rooney, CM.[2020]

The study introduces a new third-generation CAR T-cell therapy (3G.CAR33-T) targeting CD33 for treating acute myeloid leukemia (AML), showing improved viability, proliferation, and cytotoxicity compared to second-generation CAR T-cells.

3G.CAR33-T cells effectively kill CD33-positive leukemia cells while sparing normal hematopoietic stem and progenitor cells, suggesting a safer treatment option that could be combined with genome-edited stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD33-directed immunotherapy with third-generation chimeric antigen receptor T cells and gemtuzumab ozogamicin in intact and CD33-edited acute myeloid leukemia and hematopoietic stem and progenitor cells. Liu, Y., Wang, S., Schubert, ML., et al.[2022]

Up to 30% of patients with acute myeloid leukemia (AML) show some response to CAR T-cell therapy, but these responses are often not deep or long-lasting, indicating a need for improved treatment strategies.

Common targets for CAR T-cells in AML include CD123, CD33, and CLL-1, but while these therapies can lead to myeloablation and cytokine release syndrome, they rarely cause neurotoxicity, suggesting a relatively safe profile for certain side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric Antigen Receptor T Cells in Acute Myeloid Leukemia. Cummins, K., Gill, S.[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]

The development of bispecific CAR T cells targeting both CD33 and CD123 shows promise in controlling acute myeloid leukemia (AML) without causing on-target off-tumor toxicities, which is a common issue with therapies targeting these markers.

In preclinical tests using a mouse model, the bispecific CAR T cells demonstrated similar effectiveness in controlling AML as traditional monospecific CAR T cells, suggesting they could be a safer and effective treatment option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bispecific CD33/CD123 targeted chimeric antigen receptor T cells for the treatment of acute myeloid leukemia. Boucher, JC., Shrestha, B., Vishwasrao, P., et al.[2023]

Cytokine-induced killer (CIK) cells modified to express anti-CD123 CAR are effective in reducing leukemia burden in acute myeloid leukemia (AML) while sparing normal hematopoietic stem/progenitor cells, making them a safer treatment option.

In contrast, anti-CD33 CAR T cells also reduce leukemia but risk damaging normal blood cell production due to CD33 expression on healthy cells, highlighting the potential advantages of targeting CD123 in immunotherapy for AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chimeric antigen receptors against CD33/CD123 antigens efficiently target primary acute myeloid leukemia cells in vivo. Pizzitola, I., Anjos-Afonso, F., Rouault-Pierre, K., et al.[2023]

In a study testing CD33-CAR NK cells in patients with relapsed and refractory acute myeloid leukemia (AML), no significant adverse effects were observed at doses up to 5 billion cells per patient, suggesting a favorable safety profile.

CAR NK-92 cells can be produced at a lower cost than CAR T cells, indicating that with further optimization, they could become a more accessible treatment option for cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. Tang, X., Yang, L., Li, Z., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05672147

Study Details | NCT05672147 | CD33-CAR T Cell Therapy ... This phase I trial tests the safety, side effects, and the best dose of anti-CD33 chimeric antigen receptor (CAR) T-Cell therapy in treating patients with ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11938459/

Recent advances of CAR-T cells in acute myeloid leukemia This review mainly summarizes and discusses the research progress and the clinical application of CAR-T cell immunotherapy in AML in recent years.

3. sciencedirect.com sciencedirect.com/science/article/pii/S1525001625002618

CAR-T cell therapy for treatment of acute myeloid leukemia ... This review discusses the advances of CAR-T cell therapy in AML, targets, and outcomes in preclinical and clinical studies.

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.6518

Phase I study of functionally enhanced CD33 CAR T cells ... We report the safety and efficacy of functionally enhanced CD33 CAR T cells. While some patients had CRi, there was also depletion of CD33-positive normal ...

5. ehoonline.biomedcentral.com ehoonline.biomedcentral.com/articles/10.1186/s40164-024-00592-6

Safety and efficacy of CD33-targeted CAR-NK cell therapy for ... We have developed a new CAR construct that targets CD33 and modified NK cells, specifically eliminating AML cells while reducing severe side effects on stem ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39748428/

Safety and efficacy of CD33-targeted CAR-NK cell therapy ... Conclusions: Our preclinical and clinical data demonstrated the primary efficacy and safety of CD33 CAR-NK cells for patients with R/R AML.