CD33 CART Therapy for Acute Myeloid Leukemia

Not currently recruiting at 6 trial locations

Overseen By Kristi Wilmes

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Center for International Blood and Marrow Transplant Research

Must not be taking: Steroids, CAR T-cell therapy

Disqualifiers: CNS disease, Hyperleukocytosis, Pregnancy, others

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

Compensation: Varies

Number of Visits: 28

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called CD33CART (CD33-directed chimeric antigen receptor-modified T cells) for young people with acute myeloid leukemia (AML), a challenging type of blood cancer. The trial aims to determine the safety and effectiveness of this treatment, particularly for those whose cancer has returned or hasn't responded to other treatments. Participants will receive either their own modified immune cells (autologous) or cells from a donor (allogeneic) to target the cancer. This trial suits children and young adults up to 35 with AML that hasn't improved with standard treatments and who have a suitable donor available. As a Phase 1, Phase 2 trial, the research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but there are specific 'washout' periods (time without taking certain medications) for some treatments before apheresis. For example, systemic chemotherapy must be stopped 14 days before, except for certain drugs like hydroxyurea (1 day) and azacytidine/decitabine (7 days). Please consult with the trial team for guidance on your specific medications.

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

Research has shown that CD33 chimeric antigen receptor T cells (CD33CART) have been tested in trials for treating acute myeloid leukemia (AML) with promising results. In earlier studies, patients who received CD33-directed CAR-T cells generally tolerated them well, though some experienced side effects. Common side effects included fever and low blood cell counts, typical for this therapy.

CD33CART can be used in two ways: autologous, where the patient's own cells are modified and returned, and allogeneic, where the cells come from a donor. The autologous method is often considered safer because the cells originate from the patient, reducing the chance of rejection.

The safety information for allogeneic CD33CART is less complete, but researchers are actively studying it. Early results suggest it could be a viable option, though more information is needed to fully understand its risks.

As this treatment remains under investigation, especially in these early stages, researchers closely monitor safety and side effects. Joining such trials involves regular check-ups to quickly manage any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CD33CART therapy for acute myeloid leukemia because it offers a unique approach compared to traditional treatments like chemotherapy and stem cell transplants. Unlike these standard options, which generally attack rapidly dividing cells, CD33CART therapy is a type of CAR T-cell therapy that specifically targets the CD33 protein found on the surface of leukemia cells. This precision means it could potentially attack cancer cells more effectively while sparing healthy ones. Additionally, the trial includes two distinct types of CD33CART therapies: autologous, where patients receive modified versions of their own immune cells, and allogeneic, where they receive cells from a donor. This flexibility could make the treatment more accessible and effective for a broader range of patients.

What evidence suggests that CD33CART therapy could be effective for acute myeloid leukemia?

Research has shown that CD33CART therapy, which targets CD33 proteins on leukemia cells, holds promise for treating acute myeloid leukemia (AML). In lab studies, these CAR T cells have effectively attacked and killed leukemia cells, leading to longer survival in animal tests. Patients who have received CAR T treatments for similar blood cancers have experienced positive outcomes, although results can vary with AML due to its complexity. Early studies suggest that CD33-targeted CAR T cells can effectively fight AML, but challenges remain. This trial will explore both autologous (using the patient's own cells) and allogeneic (using donor cells) CD33CART methods to improve success. ^{1 2 4 6 7}

Who Is on the Research Team?

Richard Aplenc, MD, PhD

Principal Investigator

Children's Hospital of Philadelphia

Nirali N. Shah

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

This trial is for children and young adults aged 1-35 with relapsed/refractory acute myeloid leukemia (AML) that expresses CD33. Participants must have had at least one failed treatment, be eligible for a stem cell transplant, and have adequate organ function. Pregnant or breastfeeding individuals, those with certain infections or other cancers, and anyone who has recently received specific treatments are excluded.

Inclusion Criteria

My liver is working well.

My cancer has returned after a second complete remission, with more than 5% cancer cells in my bone marrow.

AST (SGOT)/ALT (SGPT) < 5 x institutional ULN (< grade 3)

Exclusion Criteria

I have taken hydroxyurea for 1 day.

I have had chemotherapy injected into my spine more than 3 days ago.

I haven't taken any experimental cancer drugs in the last 28 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1 Treatment

Determine the maximum tolerated dose of CD33CART cells using a 3+3 trial design, with dose-escalation for autologous and allogeneic arms

4 weeks

Multiple visits for dose escalation and monitoring

Phase 2 Treatment

Expansion phase to evaluate the rate of response to CD33CART

4 weeks

Regular visits for response evaluation

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

Visits at 28 days and 6 weeks post-infusion

What Are the Treatments Tested in This Trial?

Interventions

• CD33CART

Trial Overview The study tests two types of anti-CD33 CAR T-cell therapies: autologous (from the patient's own cells) and allogeneic (donor cells). It aims to find the highest dose patients can tolerate without severe side effects in Phase 1 and then assess how well the treatment works in Phase 2.

How Is the Trial Designed?

Group I: CD33CART autologous Experimental Treatment 1 Intervention

Patients who receive an autologous CD33CART cell infusion

Group II: CD33 CART allogeneic Experimental Treatment 1 Intervention

Patients who receive an allogeneic CD33CART cell infusion

Who Is Running the Clinical Trial?

Center for International Blood and Marrow Transplant Research

Lead Sponsor

Trials

40

Recruited

200,190,000+

National Marrow Donor Program

Collaborator

Trials

63

Recruited

202,000+

St. Baldrick's Foundation

Collaborator

Trials

19

Recruited

9,100+

Published Research Related to This Trial

CART33, a chimeric antigen receptor T cell therapy targeting CD33, showed significant effectiveness in eradicating acute myeloid leukemia (AML) in preclinical models, leading to prolonged survival.

To reduce the risk of long-term toxicity associated with permanent CART cell expression, a transiently expressed mRNA anti-CD33 CAR was developed, demonstrating potent but self-limited activity against AML, making it a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. Kenderian, SS., Ruella, M., Shestova, O., et al.[2022]

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]

The clinical trial involved a 41-year-old male patient with refractory acute myeloid leukemia (AML) who received 1.12 billion CD33-directed CAR-modified T cells, resulting in a significant reduction of leukemia cells in the bone marrow within 2 weeks.

Despite initial positive effects, the patient experienced severe side effects, including fever and fluctuations in blood cell counts, and the leukemia progressed again by 9 weeks, indicating the need for further research on CART-33 therapy in AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of CD33-directed chimeric antigen receptor-modified T cells in one patient with relapsed and refractory acute myeloid leukemia. Wang, QS., Wang, Y., Lv, HY., et al.[2021]

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]

CD123 is confirmed as a valid target for treating acute myeloid leukemia (AML), with both 41BB-based and CD28-based CAR T-cell therapies showing strong effectiveness in eliminating AML cells in laboratory and animal models.

However, these CAR T-cell therapies also destroy normal blood stem cells, which raises safety concerns and suggests they should primarily be used as a temporary solution before a stem cell transplant in patients with refractory or relapsed AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo. Baroni, ML., Sanchez Martinez, D., Gutierrez Aguera, F., et al.[2021]

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/NCT03971799

NCT03971799 | Study of Anti-CD33 Chimeric Antigen ... This phase 1/2 trial aims to determine the safety and feasibility of antiCD33 chimeric antigen receptor (CAR) expressing T cells (CD33CART) in children and ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10164930/

Outcomes with chimeric antigen receptor t-cell therapy in ... CAR-T therapy has demonstrated modest efficacy in RR-AML. Major challenges include heterogeneous disease biology, lack of a unique targetable ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4644600/

CD33-specific chimeric antigen receptor T cells exhibit ... CART33 exhibited significant effector functions in vitro and resulted in eradication of leukemia and prolonged survival in AML xenografts.

4. ashpublications.org ashpublications.org/blood/article/145/11/1113/534311/Honing-CAR-T-cells-to-tackle-acute-myeloid

Honing CAR T cells to tackle acute myeloid leukemia | Blood A single CD19 CAR T-cell infusion yields a complete remission (CR) in 80% of patients with B-ALL, approximately half of whom will be alive after ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1525001616300247

Treatment of CD33-directed Chimeric Antigen Receptor ... We conducted a clinical trial to assess the feasibility and efficacy of CD33-directed chimeric antigen receptor-modified T cells (CART-33) for the treatment of ...

6. nature.com nature.com/articles/s41375-021-01232-2

Autologous CD33-CAR-T cells for treatment of relapsed/ ... Remarkable results were achieved with CAR-modified T cells targeting CD19 in relapsed/refractory patients with diffuse large B cell lymphoma ( ...

7. dailynews.ascopubs.org dailynews.ascopubs.org/do/car-t-cell-therapy-myeloid-malignancies-progress-promise-and-persistent-hurdles

CAR T-Cell Therapy for Myeloid Malignancies Strategies involving CAR T cells as a bridge to transplant have provided promising results and may be performed without graft-versus-host ...