- Acute lymphoblastic leukemia (ALL) accounts for approximately 25% of childhood cancer.
Survival rates have improved, but outcomes for some subgroups, including infants and
young adults remain poor, and survival for patients who relapse is < 50%, despite
allogeneic stem cell transplant following second remission.
- CD19 immune escape has been observed by several groups following CD19-CAR therapy for
B-ALL. Investigation of this phenomenon reveals a complex biology responsible for loss
or downregulation of CD19 expression observed in these cases.
- Sequential therapy using CD22-CARs to treat CD19 dim/lo escape is associated with rapid
development of resistance due to CD22 downregulation. This trial will test whether
simultaneous targeting of CD19 and CD22 using a novel bivalent CD19/22-CAR is safe and
-Assess the safety of administering escalating doses of autologous CD19/CD22-CAR engineered T
cells that meet established release specifications in children and young adults with
CD19+CD22+ B cell ALL or lymphoma following a cyclophosphamide/fludarabine conditioning
-Patients between greater than or equal to 3 years and less than or equal to 35 years of age,
with CD19+/CD22+ B cell ALL or lymphoma who have relapsed or have refractory disease after at
least one standard chemotherapy regimen and one salvage regimen, with no alternative curative
options who meet standard Phase I eligibility criteria.
- Phase I, 3 + 3 dose escalation design using the following dose levels: -1: 1 x 10^5
transduced T cells/kg (+/- 20%); 1: 3 x 10^5 transduced T cells/kg (+/- 20%); 2: 1 x
10^6 transduced T cells/kg; and 3: 3 x 10^6 transduced T cells/kg (+/- 20%); 4: 1 x 10^7
transduced T cells/kg (+/- 20%).
- Patients will receive a lymphodepleting preparative regimen of fludarabine (25 mg/m^2/d
x 3 on Days -4, -3, -2) and cyclophosphamide (900 mg/m^2/d x 1 on Day -2) followed by
infusion of CD19/CD22-CAR T-cells on D0. Patients who are CAR pre-treated (with
exception for those with an interval HSCT) will receive increased lymphodepleting
preparative regimen of fludarabine (30 mg/m^2/d x 4 on Days -5, -4, -3, -2) and
cyclophosphamide (600 mg/m^2/d x 2 on Days -3, -2) followed by infusion of CD19/CD22-CAR
T-cells on D0.
- Patients will be evaluated sequentially for toxicity, antitumor effects, CAR expansion
and persistence, as well as research correlatives.
- INCLUSION CRITERIA:
- Patient must have a B cell ALL (inclusive of CML with ALL transformation) or
lymphoma and must have relapsed or refractory disease after at least one standard
chemotherapy regimen and one salvage regimen. In view of the PI and the primary
oncologist, there must be no available alternative curative therapies and
subjects must be either ineligible for allogeneic stem cell transplant (SCT),
have refused SCT, recurred after SCT, or have disease activity that prohibits SCT
at the time of enrollment. Patients who have undergone autologous SCT will be
eligible, and patients that have undergone allogeneic SCT will be eligible if, in
addition to meeting other eligibility criteria, they have no evidence of GVHD and
have been without immunosuppressive agents for at least 30 days. Patients with
Philadelphia chromosome + ALL must have failed prior tyrosine kinase inhibitor.
- Patients must have measurable or evaluable disease at the time of enrollment,
which may include any evidence of disease including minimal residual disease
detected by flow cytometry.
- CD22/CD19 Expression
--CD19 expression must be detected on greater than 15% of the malignant cells by
immunohistochemistry or greater than 90% by flow cytometry. The choice of whether to
use flow cytometry or immunohistochemistry will be determined by what is the most
easily available tissue sample in each patient. In general, immunohistochemistry will
be used for lymph node biopsies, flow cytometry will be used for peripheral blood and
bone marrow samples. CD22+ B cell malignancy is required and CD22 expression levels
will be documented when available, but a specific level of expression is not an
eligibility requirement; it may be documented as positive or negative.
--Greater than or equal to 3 years of age (and at least 15 kg) and less than or equal
to 35 years of age at time of enrollment (greater than or equal to 3 years to less
than or equal to 30 years). NOTE: The first patient in each dose cohort must be
greater than or equal to 18 years of age.
- Clinical Performance
--Clinical performance status: Patients greater than or equal to 16 years of age:
Karnofsky greater than or equal to 50%; Patients < 16 years of age: Lansky scale
greater than or equal to 50%. Subjects who are unable to walk because of paralysis,
but who are upright in a wheelchair will be considered ambulatory for the purpose of
calculating the performance score.
- Patients must have normal organ and marrow function as defined below:
- leukocytes greater than or equal to 750/mcL*
- platelets greater than or euqual to 50,000/mcL*
- total bilirubin less than or equal to 2 X ULN (except in the case of subjects
with documented Gilbert s disease > 3x ULN)
- AST(SGOT)/ALT(SGPT) less than or equal to 10 X institutional upper limit of
- creatinine less than or equal to the maximum for age listed in the table below
- creatinine clearance greater than or equal to 60 mL/min/1.73 m2 for patients with
creatinine levels above institutional normal.
- Age: less than or equal to 5. Maximun Serum Creatinine (mg/dL): less than or equal to
- Age: 6 to less than or equal to 10. Maximum Serum Creatinine (mg/dL): less than or
equal to 1.0
- Age: >10. Maximum Serum Creatinine (mg/dL): less than or equal to 1.2
* if these cytopenias are not judged by the investigator to be due to underlying
disease (i.e. potentially reversible with anti-neoplastic therapy); A subject will not
be excluded because of pancytopenia greater than or equal to Grade 3 if it is due to
disease, based on the results of bone marrow studies.
- a. Subjects with leukemia with the following CNS status are eligible only in the
absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve
- CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin
preparation, regardless of the number of WBCs;
- CNS 2, defined as presence of < 5/uL WBCs in CSF and cytospin positive for
blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm:
- CNS 2a: < 10/uL RBCs; < 5/uL WBCs and cytospin positive for blasts;
- CNS 2b: greater than or equal to 10/uL RBCs; less than or equal to 5/uL WBCs
and cytospin positive for blasts;
- CNS 2c: greater than or equal to 10/uL RBCs; greater than or equal to 5/uL
WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer
- b. Subjects with lymphoma
---Subjects must have no signs or symptoms of CNS disease or detectable evidence of
CNS disease on MRI at the time of screening. Subjects who have been previously treated
for CNS disease but have no evidence of disease at screening are eligible.
- Patients of child-bearing or child-fathering potential must be willing to practice
birth control from the time of enrollment on this study and for four months after
receiving the preparative regimen.
- Cardiac function: Left ventricular ejection fraction greater than or equal to 45%
or fractional shortening greater than or equal to 28%, and no clinically
significant ECG findings
- Pulmonary Function
- Baseline oxygen saturation >92% on room air at rest
- Patients with respiratory symptoms must have a DLCO/adjusted > 45%. For children
who are unable to cooperate for PFTs they must not have dyspnea at rest or known
requirement for supplemental oxygen.
- Ability of subject or Legally Authorized Representative (LAR) to understand and
the willingness to sign a written informed consent document.
For subjects <18 years old their legal guardian must give informed consent. Pediatric
subjects will be included in age appropriate discussion and verbal assent will be obtained
for those > 7 years of age, when appropriate.
Subjects meeting any of the following criteria are not eligible for participation in the
- Recurrent or refractory ALL limited to isolated testicular or isolated central nervous
system (CNS) disease.
- Subjects with radiologically-detected CNS lymphoma or CNS 3 disease (presence of
greater than or equal to 5/micro L WBCs in CSF and cytospin positive for blasts [in
the absence of a traumatic lumbar puncture] and/or clinical signs of CNS leukemia
and/or radiographic signs of leptomeningeal disease);
- Hyperleukocytosis (greater than or equal to 50,000 blasts/micro L) or rapidly
progressive disease that in the estimation of the investigator and sponsor would
compromise ability to complete study therapy;
- Pregnant women are excluded from this study because the study agents have the
potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with the study agents, breastfeeding should be discontinued.
- Subjects will be excluded related to the following prior therapy criteria:
- Systemic chemotherapy, anti-neoplastic investigational agents, or antibody based
therapies =<2 weeks (6 weeks for clofarabine or nitrosoureas) prior to apheresis
with the following exception:
---No time restricution with prior intrathecal chemotherapy, steroid therapy,
hydroxyurea or ALL maintenance type chemotherapy (vincristine, 6-mercaptopurine,
oral methotrexate, or a tyrosine kinase inhibitor for patients with Ph+ ALL)
provided there is recovery from any acute toxic effects.
- Radiation therapy =<3 weeks prior to apheresis with the following exception:
---No time restriction with radiation therapy if the volume of bone marrow
treated is less than 10% and the subject has measureable/evaluable disease
outside the radiation window.
- History of allogeneic stem cell transplantation prior to apheresis that meet the
- Less than 100 days post-transplant
- Evidence of active graft-verus-host disease (GVHD)
- Taking immunosuppressive agents within 30 days prior to apheresis
- Less than 6 weeks post donor lymphocyte infusion (DLI)
- History of prior CAR therapy or other adoptive cell therapies prior to apheresis
that meet the following criteria:
- Less than 30 days post-infusion
- Circulating CAR T cells (or genetically modified cells) >5% by flow
cytometry in peripheral blood.
- HIV/HBV/HCV Infection:
- a. Seropositive for HIV antibody. (Patients with HIV are at increased risk of
lethal infections when treated with marrow-suppressive therapy. Appropriate
studies will be undertaken in patients receiving combination antiretroviral
therapy in the future should study results indicate effectiveness.)
- b. Seropositive for hepatitis C or positive for Hepatitis B surface antigen
- Uncontrolled, symptomatic, intercurrent illness including but not limited to
infection, congestive heart failure, unstable angina pectoris, cardiac arrhythmia,
psychiatric illness, or social situations that would limit compliance with study
requirements or in the opinion of the PI would pose an unacceptable risk to the
- Second malignancy other than in situ carcinoma of the cervix, unless the tumor was
treated with curative intent at least two years previously and subject is in
- History of severe, immediate hypersensitivity reaction attributed to compounds of
similar chemical or biologic composition to any agents used in study or in the
manufacturing of the cells.