This phase 1/2 study is testing a new treatment for acute myeloid leukemia (AML) that has come back or has not responded to other treatments. The treatment uses specially modified immune cells (called CD33 CAR-NK cells) from a healthy, unrelated donor to attack the cancer.
The first part of the study (Phase I) will focus on finding the safest and most effective dose. The second part (Phase II) will test how well the treatment works at that dose.
Patients will undergo screening, chemotherapy (Fludarabine and Cytarabine, in combination with Venetoclax) followed by the infusion of the CD33 CAR NK cells. Some patients may receive 2 doses of CD33 CAR NK cells infused 1 week apart. The investigator will let participants know if they will receive 1 or 2 doses. Patients will be hospitalized for the chemotherapy and CD33 CAR NK cell infusion for close monitoring and will remain in the hospital until blood counts recover. If patients are discharged from the hospital before day 35, they will be followed in clinic weekly for blood work and a physical exam.
A bone marrow biopsy will be performed around day 28-35 to see if the patient's leukemia is in remission. Lumbar puncture or imaging may also be done if the study doctor thinks it is necessary.
Patients will continue to be followed for research studies and clinical outcomes (leukemia relapse, survival) for 1 year. After 1 year, patients will have completed their study participation, but can be monitored for up to 15 years for potential long term side effects of the cell therapy. Some patients may undergo a bone marrow transplant after the study treatment. Patients who proceed to bone marrow transplant will have one blood sample drawn about a month after the transplant and then will have completed study participation.
Patients with relapsed AML (patients in second or subsequent relapse, or any relapse after HSCT, are eligible).
Refractory AML defined as failure to achieve a complete response after 2 cycles of induction or reinduction chemotherapy, including persistent MRD positivity.
Patients with isolated CNS or extramedullary disease are eligible. Patients with CNS disease are excluded from the phase I dose escalation portion but are eligible for the phase II portion of the study.
1-39.99 years of age (note: the first three subjects treated AND the first subject on each dose level must be ≥ 16 years of age)
AML directed therapies in the 14 days prior to beginning treatment on this protocol (except for hydroxyurea) Note: There is no waiting period required for patients having received intrathecal cytarabine, methotrexate and/or hydrocortisone
Gemtuzumab or other CD33-targeted antibody within 42 days of enrollment
CNS radiation within 28 days of enrollment
DLI or adoptive cell therapy within 30 days of enrollment
Single group
Universal donor derived CD33 CAR-NK
Biological/VaccineUniversal donor derived CD38KO CD33 CAR-NK manuctured on-site. The NK cells are derived from the peripheral blood of universal donors with desirable HLA/KIR types and CMV status, modified by CRISPR/Cas9 targeting the CD38 locus, using AAV6 vector to insert a CD33-targeted CAR gene into the CD38 locus, and expanded in number.
Phase I : Safety and recommended phase 2 dose
To determine the safety and recommended phase 2 dose of CD33 CAR-NK cells in patients with relapsed/refractory AML investigators will monitor the incidence and severity of adverse events and the rate of dose limiting toxicities.
Phase II: Efficacy of CD33 CAR NK cells
To estimate the efficacy of CD33 CAR-NK cells delivered at the RP2D with FLA-VEN chemotherapy, the investigators will determine the complete response rate.
Overall survival, event free survival and duration of remission
To estimate the overall survival, event free survival, and duration of remission in patients who do not proceed to HSCT.
Depth of remission
To determine the percentage of patients who achieve molecular remission and/or MRD negative remission by flow cytometry.
Events of special interest
To determine the rate of events of special interest including: Cytokine Release Syndrome, Immune Effector Cell Neurotoxicity Syndrome, Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome, hepatic VOD, primary graft failure (in patients who undergo HSCT)
Neutrophil recovery
To evaluate the median time to neutrophil and platelet recovery
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