CD33 CART Therapy for Acute Myeloid Leukemia

Recruiting in Palo Alto (17 mi)

+6 other locations

Overseen by Richard Aplenc, MD, PhD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

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

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.

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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.

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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.

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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.

Trial 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

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Seattle Children's Hospital/ Fred Hutchinson Cancer Research Center Seattle, WA

Seattle Children's Hospital/Fred Hutchinson Cancer Research Center Seattle, WA

Dana-Farber Cancer Institute Boston, MA

The Children's Hospital of Philadelphia Philadelphia, PA

More Trial Locations

Who Is Running the Clinical Trial?

Center for International Blood and Marrow Transplant Research Lead Sponsor

National Marrow Donor Program Collaborator

St. Baldrick's Foundation Collaborator

References

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

Anti-CD33 chimeric antigen receptor targeting of acute myeloid leukemia. [2021] Current therapies for acute myeloid leukemia are associated with high failure and relapse rates. Adoptive immunotherapies, which have shown promise in the treatment of hematologic malignancies, have the potential to target acute myeloid leukemia through pathways that are distinct and complementary to current approaches. Here, we describe the development of a novel adoptive immunotherapy specific for this disease. We generated a second generation CD33-specific chimeric antigen receptor capable of redirecting cytolytic effector T cells against leukemic cells. CD33 is expressed in approximately 90% of acute myeloid leukemia cases and has demonstrated utility as a target of therapeutic antibodies. Chimeric antigen receptor-modified T cells efficiently killed leukemia cell lines and primary tumor cells in vitro. The anti-leukemia effect was CD33-specific, mediated through T-cell effector functions, and displayed tumor lysis at effector:target ratios as low as 1:20. Furthermore, the CD33-redirected T cells were effective in vivo, preventing the development of leukemia after prophylactic administration and delaying the progression of established disease in mice. These data provide pre-clinical validation of the effectiveness of a second-generation anti-CD33 chimeric antigen receptor therapy for acute myeloid leukemia, and support its continued development as a clinical therapeutic.

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] 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 refractory acute myeloid leukemia (AML). A 41-year-old male patient with AML was enrolled and received a total of 1.12 × 10(9) autologous CART-33 cells, of which ~38% were transduced with CAR. The CART-33 infusion alone induced rigorous chills and fevers; drastic fluctuations of his preexisting pancytopenia; elevated serum cytokine levels, including interleukin (IL)-6, IL-8, tumor necrosis factor-α, and interferon-γ; slight transient hyperbilirubinemia within 2 weeks; a subsequent intermittent moderate fever; and reversed fluctuation of the pancytopenia. A marked decrease of blasts in the bone marrow was observed on examination 2 weeks after therapy, and there was a gradual increase until florid disease progression occurred at 9 weeks after the cell infusion. These observations warrant further research on CART-33 treatment in refractory AML and may spur efforts to extend the CART-33-induced tumor burden to the preparation of other intensive strategies, such as hematopoietic stem cell transplantation. This study is registered at www.ClinicalTrials.gov as NCT01864902.

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

CD33-specific chimeric antigen receptor T cells exhibit potent preclinical activity against human acute myeloid leukemia. [2022] Patients with chemo-refractory acute myeloid leukemia (AML) have a dismal prognosis. Chimeric antigen receptor T (CART) cell therapy has produced exciting results in CD19+ malignancies and may overcome many of the limitations of conventional leukemia therapies. We developed CART cells to target CD33 (CART33) using the anti-CD33 single chain variable fragment used in gemtuzumab ozogamicin (clone My96) and tested the activity and toxicity of these cells. CART33 exhibited significant effector functions in vitro and resulted in eradication of leukemia and prolonged survival in AML xenografts. CART33 also resulted in human lineage cytopenias and reduction of myeloid progenitors in xenograft models of hematopoietic toxicity, suggesting that permanently expressed CD33-specific CART cells would have unacceptable toxicity. To enhance the viability of CART33 as an option for AML, we designed a transiently expressed mRNA anti-CD33 CAR. Gene transfer was carried out by electroporation into T cells and resulted in high-level expression with potent but self-limited activity against AML. Thus our preclinical studies show potent activity of CART33 and indicate that transient expression of anti-CD33 CAR by RNA modification could be used in patients to avoid long-term myelosuppression. CART33 therapy could be used alone or as part of a preparative regimen prior to allogeneic transplantation in refractory AML.

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

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo. [2021] Acute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity. CD33-redirected and CD123-redirected CARTs for AML are in advanced preclinical and clinical development, and they exhibit robust antileukemic activity. However, preclinical and clinical controversy exists on whether such CARTs are myeloablative.

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] Immunotherapies, such as chimeric antigen receptor (CAR) modified T cells and antibody-drug conjugates (ADCs), have revolutionized the treatment of cancer, especially of lymphoid malignancies. The application of targeted immunotherapy to patients with acute myeloid leukemia (AML) has been limited in particular by the lack of a tumor-specific target antigen. Gemtuzumab ozogamicin (GO), an ADC targeting CD33, is the only approved immunotherapeutic agent in AML. In our study, we introduce a CD33-directed third-generation CAR T-cell product (3G.CAR33-T) for the treatment of patients with AML. 3G.CAR33-T cells could be expanded up to the end-of-culture, that is, 17 days after transduction, and displayed significant cytokine secretion and robust cytotoxic activity when incubated with CD33-positive cells including cell lines, drug-resistant cells, primary blasts as well as normal hematopoietic stem and progenitor cells (HSPCs). When compared to second-generation CAR33-T cells, 3G.CAR33-T cells exhibited higher viability, increased proliferation and stronger cytotoxicity. Also, GO exerted strong antileukemia activity against CD33-positive AML cells. Upon genomic deletion of CD33 in HSPCs, 3G.CAR33-T cells and GO preferentially killed wildtype leukemia cells, while sparing CD33-deficient HSPCs. Our data provide evidence for the applicability of CD33-targeted immunotherapies in AML and its potential implementation in CD33 genome-edited stem cell transplantation approaches.

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] CAR T cells have shown clinical efficacy for acute lymphoblastic leukemia, but this therapy has not been effective for acute myeloid leukemia (AML), and other treatment options are needed. Theoretically, CAR-NK cells have a more favorable toxicity profile compared to CAR T cells, especially in avoiding adverse effects such as cytokine release syndrome. However, the clinical evidence for this has not yet been reported. In the current study, we tested the safety of CD33-CAR NK cells in patients with relapsed and refractory AML. At doses up to 5 &#215; 109 (5 billion) cells per patient, no significant adverse effects were observed. CAR NK-92 cells can be produced at much lower cost compared to CAR T cells, and we believe after being optimized, they will be widely accessible for the treatment of cancer.