This study is designed as a single arm open label traditional Phase I, 3+3, study of CD4-redirected chimeric antigen receptor engineered T-cells (CD4CAR) in subjects with relapsed or refractory AML. The study will evaluate safety in this subject population and also the presence of efficacy signal described by elimination of residual disease to qualify subjects for stem cell transplant.
≥ 12 years old at the time of informed consent
Ability to provide written informed consent and HIPAA authorization.
Diagnosis of AML that is CD4+ and must have failed standard induction/ first line treatment such as intensive induction or less intensive hypomethylation and venetoclax first line. In the specific case of azacitidine and venetoclax (aza/ven), BM biopsy for response assessment on days 21-28 of first cycle. If disease progression by increasing number of blasts is documented, subject will be eligible. If no morphologic remission (persistent BM blasts above 5%) but evidence of efficacy exists, a second cycle without interruption will be given with the goal of achieving morphologic remission and repeat BM biopsy on days 21-28 of this cycle. If residual disease or disease progression is captured, then they will be considered refractory and will qualify for this trial. This is unless the subject now qualifies for a more intensive induction therapy that they did not qualify for when aza/ven was initially chosen as first-line treatment. Given the low response rate for aza/ven in the RR-AML, CR of only 13%, this combination would not be a prerequisite to qualify for the study.
Creatinine clearance of > 60ml/min (or otherwise non clinically significant, per study investigator)
CD4 negative AML
Pregnant or lactating women. The safety of this therapy on unborn children is not known. Female study participants of reproductive potential (see definition below) must have a negative serum or urine pregnancy test prior to initiation of conditioning chemotherapy, per research sites' clinical policy.
Uncontrolled active infection necessitating systemic therapy.
Active hepatitis B hb, or hepatitis C, HC, infection. Active hepatitis C is defined as the hepatitis C antibody is positive while quantitative HCV RNA results exceed the lower detection limit.
Single group
CD4CAR
Biological/VaccineCD4CAR cells transduced with a lentiviral vector to express the single-chain variable fragment (scFv) nucleotide sequence of the anti-CD4 molecule derived from humanized monoclonal ibalizumab and the intracellular domains of CD28 and 4-1BB co-activators fused to the CD3ζ T-cell activation signaling domain administered by IV infusions as a single dose
1. Dose finding: Maximum tolerated dose (MTD) is defined as one dose level lower than the Dose Limiting Toxicity (DLT) of the CD4CAR in AML. Optimal dose is highest safe dose that produces the most response.
In this traditional phase 1 dose escalation, cohorts of three subjects will be treated on a dose level that will be incremented to next dose level if no dose limiting toxicities (DLT) were reported or expanded if a DLT is documented.
Persistence and biologic behavior of CD4CAR as measured by a. Serial blood and marrow sampling to detect CD4CAR over time post infusion. b. Serial testing for CD4CAR proliferation, differentiation and polarization if feasible overtime after infusion.
The persistence of the CAR through day 28 and possibly longer if detected by D28. This will be performed by flow to assess for the CD3+/Fab2+ cell population The phenotype of the CAR will be determined by flow as well, to look for Tcm phenotype
3. Determine the influence of CD4CAR on T regs
1. Examine the efficacy of CD4CAR on changing the frequency of T regs subpopulation after CD4CAR infusion as compared to their frequency prior to treatment. 2. Determine the impact of the change in T regs and MDSCs abundance on objective response to CD4CAR.
Determine the influence of CD4CAR on myeloiod derived suppressor cells, MDSCs
Examine the efficacy of CD4CAR on changing the frequency of MDSCs subpopulation
Determine mLSCs frequency before and after the CD4CAR infusion
Participants' blood will be tested by flow cytometry to determine the ability of CD4CAR to target Monocytic Leukemia Stem Cells (mLSCs).
Quantification of CD4CAR associated cytokines
Participants blood will be examined for cytokine level changes according to time points as described in the protocol.
Describe disease response using European LeukemiaNet (ELN) 2022 recommendation
Treatment is intended to reduce the disease burden enough to qualify subjects for stem cell transplant through either elimination of residual disease or minimizing that to being acceptable to transplant consideration. For response evaluation of the frequency of successful bridging to transplant, European LeukemiaNet (ELN) 2022 recommendation will be applied.
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