CD33 CART Therapy for Acute Myeloid Leukemia

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

52 Participants Needed

Trial Summary

What is the purpose of this trial?

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 adolescents/young adults (AYAs) with relapsed/refractory acute myeloid leukemia (AML). The trial will be done in two phases: Phase 1 will determine the maximum tolerated dose of CD33CART cells using a 3+3 trial design, with dose-escalation for autologous products separated from dose-escalation for an allogeneic arm. Phase 2 is an expansion phase designed to evaluate the rate of response to CD33CART.

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.

What data supports the effectiveness of the CD33 CAR T-cell treatment for acute myeloid leukemia?

Research shows that CD33 CAR T-cell treatment can effectively target and kill leukemia cells in laboratory and animal studies. In one patient, this treatment led to a significant reduction in leukemia cells in the bone marrow, although the disease progressed later. These findings suggest potential benefits, but more research is needed to confirm its effectiveness. ^{1 2 3 4 5}

Is CD33 CAR T-cell therapy safe for humans?

CD33 CAR T-cell therapy has shown potential in treating acute myeloid leukemia, but it can cause significant side effects like myelosuppression (reduced blood cell production) due to its impact on normal blood cells. However, a study on CD33-CAR NK cells, a related therapy, found no significant adverse effects at tested doses, suggesting a potentially safer alternative. ^{1 3 4 5 6}

How is CD33 CART therapy different from other treatments for acute myeloid leukemia?

CD33 CART therapy is unique because it uses genetically modified T cells to specifically target and kill leukemia cells that express the CD33 protein, which is present in about 90% of acute myeloid leukemia cases. This approach is different from traditional chemotherapy as it offers a targeted immunotherapy option, potentially reducing relapse rates and improving outcomes for patients with chemo-refractory AML. ^{1 2 3 4 5}

Research Team

Richard Aplenc, MD, PhD

Principal Investigator

Children's Hospital of Philadelphia

Nirali N. Shah

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia. [2021]

2. United States 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. [2021]

3. England pubmed.ncbi.nlm.nih.gov

CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. [2022]

4. England pubmed.ncbi.nlm.nih.gov

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo. [2021]

5. United States 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. [2022]

6. United States 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. [2021]