This study is designed as a single arm open label Phase I, 3x3, multicenter study of
CD4-directed chimeric antigen receptor engineered T-cells (CD4CAR) in patients with relapsed
or refractory T-cell leukemia and lymphoma. Specifically, the study will evaluate the safety
and tolerability of CD4CAR T-cells. Funding Source - FDA OOPD
The study will be performed as a dose-escalation protocol. Due to the relatively low
incidence and prevalence of cluster of differentiation 4-positive (CD4+) hematological
malignancies and the associated aggressive nature of these diseases and the sequel of
treatment failure, the investigators expect to recruit 20 subjects at Stony Brook with an
expected dropout rate of 25% primarily due to rapid progression or death and screen and or
manufacturing failure. Taking this into account, the investigators expect to treat 15
patients. The study will utilize autologous CD4CAR T-cells that are engineered to express a
chimeric antigen receptor (CAR) targeting CD4 that is linked to the cluster of
differentiation 28 (CD28), 4-1BB, cluster of differentiation 3-zeta (CD3ζ) signaling chains
(third generation CAR).
At entry, disease status will be staged and investigators will determine if the subject has
the minimal T cell number adequate for apheresis (screening step) and for manufacturing
CD4CAR cells. qualifying subjects will be leukapheresed to obtain large numbers of peripheral
blood mononuclear cells (PBMC) for the manufacturing. Next, participants will receive
conditioning chemotherapy. If tumor burden is sufficiently reduced (screening step),
participants will receive CD4CAR cells by infusion on Day 0 of treatment.
For cell harvest, 12-15-liter apheresis procedure will be performed at the apheresis center
with the intention to harvest at least 50x10^9-nucleated cells to manufacture CD4CAR T-cells.
A portion of the pheresed cells will also be cryopreserved for FDA look-back requirements and
for further research. The T-cells will be purified from the PBMC, transduced with CD4CAR
lentiviral vector, expanded in vitro, and then frozen for administration. Each dose will be
stored in either one or two bags. The route of administration is by IV infusion and the
duration of infusion will be approximately 20 minutes. Each bag will contain an aliquot
(30-50 mL) of liquid suitable for freezing, and containing the following infusible grade
reagents (% v/v): 62.5cc Plasmalyte-A 5% dextrose; 7.5cc Pure dimethylsulfoxide (DMSO), 20cc
of 25% Human Serum Albumin, and 10cc Dextran 40. The cell product is expected to be ready for
release approximately 3-4 weeks after apheresis.
If the disease progresses during the manufacturing period participants may be excluded from
the study. Minimal chemotherapy to keep the disease under control in the meanwhile is allowed
if deemed necessary by investigators.
A single dose of CD4CAR transduced T cells will consist of the cell number for the dose level
to be infused.
Post-infusion monitoring: on days 1, 3, 5, 7, 14, and 28 following infusion of CD4CAR
T-cells, evaluation of leukemic cell killing and CD4CAR Trafficking will be done. Cytokines
levels will be evaluated on Day 2, 4, 7, 11, 14, 21, 28 and every 8 hours during active
cytokine release syndrome (CRS). Active monitoring of fungal and viral infections during
treatment while utilizing standard prophylaxis recommended for HIV-positive patients with
T-cell aplasia and those undergoing allogeneic stem cell transplant. Investigators plan to
collect data about clinicoradiologic measurements of residual tumor burden starting on day 6
and weekly afterward until remission and then monthly for 6 months. This will be followed by
quarterly clinical evaluations for the next two (2) years with a medical history, physical
examination, and comprehensive blood testing. After these short- and intermediate-term
evaluations are performed, these patients will enter a rollover study to assess for
disease-free survival (DFS), relapse, and the development of other health problems or
malignancies for annual where follow-up will by phone and a questionnaire for an additional
thirteen (13) years. The treating physician will decide to proceed with allogeneic or
autologous transplant when needed.
Dose of CD4CAR description: the main objective of this study is to establish a recommended
dose and/or schedule of CD4CAR. The guiding principle for dose escalation in phase I is to
avoid unnecessary exposure of patients to sub-therapeutic doses (i.e., to treat as many
patients as possible within the therapeutic dose range) while preserving safety and
maintaining rapid accrual. Investigators will use the rule-based traditional Phase I "3+3"
design for the evaluation of safety. Based on lab experience in mice the starting dose (dose
level 1) for the first cohort of three patients in phase I portion of the study will be
8x10^5 cells. The dose escalation or de-escalation will follow a modified Fibonacci sequence
If more than one patient out of the first cohort of three patients in dose level 1 experience
dose limiting toxicity (DLT), the trial will be placed on hold. If zero or one out of three
patients in the first cohort of dose level 1 experience DLT, three more patients will be
enrolled at dose level 1; the dose escalation continues until at least two patients among a
cohort of six patients experience DLT (i.e., ≥33% of patients with a DLT at this dose level)
- If one of the first three patients in dose level 1 experiences a DLT, three more
patients will be treated at dose level 1.
- If none of the three patients or only one of the 6 patients in the dose level 1
experiences a DLT, the dose escalation continues to the dose level 2
- If one of the first three patients in dose level 2 experience a DLT, three more patients
will be treated at dose level 2
- If none of the three patients or only one of the 6 patients in the dose level2
experiences a DLT, the dose escalation continues to the dose level 3
- If one of the first three patients in dose level 3 experiences a DLT, three more
patients will be treated at dose level 3
- If none of the three patients or only one of the 6 patients in the dose level 3
experiences a DLT, dose level 3 will be declared the maximum tolerated dose (MTD) and
will be used as the recommended phase II dose (RP2D) for the phase II portion of the
In summary, the dose escalation continues until at least two patients among a cohort of six
patients experience DLT (i.e., ≥33% of patients with a DLT at that dose level). The
recommended dose for phase II trials is defined as one dose level below this toxic dose
level. Since some grade 3 and possibly 4 toxicities are highly likely to be reversible, grade
3 infectious, hematological and vascular toxicities will not be considered DLTs mandating
dose reduction. Also allergic or infusion-related reactions ≤ grade 3 will not be counted as
DLTs. There will be no intra-patient dose escalation or reduction.
To allow for full spectrum toxicity duration evaluation and reporting, no patients within the
same or a different cohort will be initiated on lymphodepleting chemotherapy sooner than 28
days from the initiation date of the preceding patient.
In order to be eligible to participate in this study, an individual will be enrolled if
they meet the following criteria:
1. Patients must voluntarily sign and date informed consent forms that state his or her
willingness to comply with all study procedures and availability for the duration of
2. Subjects with documented CD4+ hematologic malignancies. Male and female subjects with
CD4+ T-cell malignancies with either relapsed or refractory disease (including those
patients who have undergone a prior transplant and patients with an inadequate
response after 4-6 cycles of standard chemotherapy)
3. Patients who present with CD4+ Leukemia. Either relapsed disease or minimal residual
disease (MRD); any of the following are eligible:
3.1 Peripheral T-cell leukemia, NOS 3.2 T-cell prolymphocytic leukemia 3.3 Adult
T-cell leukemia 3.4 T-cell large granular lymphocytic leukemia 3.5 T cell acute
lymphoblastic leukemia (T-ALL)
4. For patients with CD4+ Lymphoma. Either relapsed or refractory disease; any of the
following are eligible:
4.1 Peripheral T-cell lymphoma, not otherwise specified (NOS) 4.2 Sezary
syndrome/cutaneous T-cell lymphoma 4.3 Angioimmunoblastic T-cell lymphoma 4.4 Adult
5. Age 18 years old or older
6. Creatinine clearance of > 60 ml/min
7. Liver enzymes < 3 x upper limit of normal
8. Bilirubin < 2.0 mg/dL
9. Serum albumin of ≥ 3gms/dl
10. Pulmonary Function Test (PFT) with diffusing capacity of lung for carbon monoxide
(DLCO) of ≥ 60%.
11. Adequate echocardiogram with ejection fraction (EF) of ≥50%
12. Adequate venous access for apheresis and no other contraindications for leukapheresis
Eligibility for CD4CAR infusion
1. No evidence of an active or uncontrolled infection for at least 72 hours
2. Afebrile and not receiving antipyretics
3. If previous history of corticosteroid chemotherapy, subject must off all but
adrenal replacement doses
4. Repeat baseline indicates presence of disease but not rapidly progressing
5. Specific organ functional criteria for cardiac, renal, and liver function similar
to initial inclusion are met. Tests such as echocardiogram and PFTs need not be
repeated if within 6 weeks of initial assessment
6. Negative pregnancy testing (if applicable)
First point screen failure: Inadequate T- lymphocytes for apheresis defined as T cell count
at screening that does not meet the requirement of ≥ 107-135/µ/L
Second point screen failure: Failure of cytoreduction with conditioning chemotherapy and
persistence of clinical high disease burden defined as extensive lymph node enlargement
that is not reduced at least by 50% of original size, presence of central nervous system
(CNS) disease or bone marrow replacement with ≥50% malignant cells.
1. Pregnant or lactating women. The safety of this therapy on unborn children is not
known. Female study participants of reproductive potential must have a negative serum
or urine pregnancy test performed within 48 hours before infusion.
2. Uncontrolled active infection.
3. Active hepatitis B or hepatitis C infection.
4. Concurrent use of systemic glucocorticoids in greater than replacement doses. Recent
or current use of inhaled glucocorticoids is not exclusionary
5. Previously treatment with any gene therapy products.
6. Feasibility assessment during screening demonstrates < 30% transduction of target
lymphocytes, or insufficient expansion (< 5-fold) in response to cluster of
differentiation 3 (CD3)/CD28 costimulation. A total of three attempts will be carried
out before deemed inadequate manufacturing
7. Any uncontrolled active medical disorder that would preclude participation as
8. HIV infection.
9. Steroid dependency for any reason as well as the potential need to treat concomitant
illnesses with steroids during the trial period, examples are patients with chronic
obstructive pulmonary disease (COPD) and asthma known to require steroids to abort
10. Patients declining to consent for treatment