This study is designed as a single arm open label traditional Phase I, 3+3, study of CD4-directed chimeric antigen receptor engineered T-cells (CD4CAR) in subjects with relapsed or refractory CMML. Specifically, the study will evaluate the safety and feasibility of CD4CAR T-cells.
≥ 18 years old at the time of informed consent
Ability to provide written informed consent and HIPAA authorization
Diagnosis of CMML that is CD4+ and is recurrent or refractory to first line standard of care treatment.
Creatinine clearance of ≥ 60 ml/min (or otherwise non clinically significant, per study investigator)
CD4 negative CMML
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 or hepatitis C 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
Dose finding: Maximum tolerated dose (MTD) is defined as one dose level lower than the dose limiting toxicity (DLT) of the CD4CAR in CMML
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
The efficacy of treatment with CD4CAR and description of CMML response to CD4CAR
serial marrow sampling will be analysed for response as measured by reduction on the CMML clonal cells at different time points. Other measures include reduction on transfusion dependency and molecular remissions if at diagnoosis molecular markers were identified.
in vivo persistence of a single dose of the CD4CAR in subjects with CMML
Flowcytometry and transgene copy number by PCR will be used to evaluate the CAR T cell persistence post infusion
efficiacy of the CD4CAR to target T regulatory cells and myeloid derived suppressor cells
T regs estimation in marrows will be done at diagnosis and on Day 28 post-infusion. This will be done by flowcytometry to assess the reduction on these cells phenotyped by double positivity for CD4 and FOXP3. At the same time points Myeloid Derived Suppressor Cells (MDSCs), will also be quantified. MDSCs will be identified by a master mix of commercially available antibodies against MDSC subsets including CD16, CD15, CD14, CD45, CD84.etc, Cytek® cFluor® MDSC Ki panel.
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Huda Salman
Lead sponsor
Indiana University
Sponsor institution
iCell Gene Therapeutics
Collaborator
The Leukemia and Lymphoma Society
Collaborator
