Inclusion criteria.
1. Disease Status
1. Disease Status of ALL
- Must have chemotherapy refractory disease defined as progression or stable
disease after two lines of therapies, or relapsed disease after achieving
CR.
- Subjects with persistent or relapsed minimal residual disease (MRD) (by flow
cytometry, PCR, FISH, or next generation sequencing) require verification of
MRD on two occasions at least 2 weeks apart.
- Subjects with Philadelphia Chromosome positive acute lymphoblastic leukemia
(Ph+ALL) are eligible if they progressed, had stable disease or relapsed
after two lines of therapy, including tyrosine kinase inhibitors (TKIs).
- Subjects with recurrence of isolated CNS relapse after achieving complete
remission (CR) are eligible.
2. Disease Status of aggressive B-cell NHL •Histologically confirmed aggressive B
cell NHL including the following types defined by WHO 2008: oDLBCL not otherwise
specified; T cell/histiocyte rich large B cell lymphoma; DLBCL associated with
chronic inflammation; Epstein Barr virus (EBV)+ DLBCL of the elderly; OR oprimary
mediastinal (thymic) large B cell lymphoma; OR otransformation of follicular
lymphoma, marginal zone lymphoma or chronic lymphocytic leukemia/small
lymphocytic lymphoma to DLBCL; OR oFollicular Lymphoma Grade 3B •Subjects with
DLBCL, Follicular Lymphoma Grade 3B -or-
Subjects with transformed FL, MZL, or CLL/SLL who HAVE NOT received chemotherapy prior
to transformation:
oMust have received an anthracycline regimen and an anti CD20 monoclonal antibody
(unless documented CD20-negative) and be refractory or relapsed after second line of
DLBCL treatment. Subjects with a partial response to second line therapy must be
ineligible for autologous transplant.
•Subjects with transformed FL, MZL, or CLL/SLL who HAVE received
anthracycline-containing chemotherapy prior to transformation: oMust have progressed,
had SD or recurred with transformed disease after initial treatment for DLBCL.
2. Measureable Disease
- Subjects with ALL: must have evaluable or measurable disease (MRD positive by
flow cytometry, NGS, or PCR is acceptable).
- Subjects with aggressive B-cell NHL: must have evaluable or measurable disease
according to the revised IWG Response Criteria for Malignant Lymphoma[38].
Lesions that have been previously irradiated will be considered measurable only
if progression has been documented following completion of radiation therapy.
3. CD22 expression
•Subjects with ALL: CD22 positive expression on malignant cells is required and must
be detected by immunohistochemistry or 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 subject.
CD22 expression must be demonstrated subsequent to any anti-CD22 targeted therapy
(e.g. Moxetumomab pasudotox or inotuzumab ogozamicin) in subjects with ALL.
•Subjects with aggressive B-cell NHL: CD22 expression at any level, including
undetectable, will be acceptable. Subjects must have archival tissue available for
analysis of CD22 expression or must be willing to undergo a biopsy of easily
accessible disease.
4. Prior Bone Marrow-Stem Cell Transplant Subjects who have undergone autologous SCT with
disease progression or relapse following SCT are eligible. Subjects who 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.
5. Prior Therapy Wash-out At least 2 weeks or 5 half lives, whichever is shorter, must
have elapsed since any prior systemic therapy at the time the subject is planned for
leukapheresis, except for systemic inhibitory/stimulatory immune checkpoint therapy,
which requires 5 half lives.
Exceptions:
1. There is no time restriction with regard to prior intrathecal chemotherapy
provided there is complete recovery from any acute toxic effects of such;
2. Subjects receiving hydroxyurea may be enrolled provided there has been no
increase in dose for at least 2 weeks prior to starting apheresis;
3. Subjects who are on standard ALL maintenance type chemotherapy (vincristine,
6-mercaptopurine or oral methotrexate) may be enrolled provided that chemotherapy
is discontinued at least 1 week or 5 half lives, whichever is shorter, prior to
apheresis.
4. Subjects receiving steroid therapy at physiologic replacement doses only are
allowed provided there has been no increase in dose for at least 2 weeks prior to
starting apheresis;
5. For radiation therapy: Radiation therapy must have been completed at least 3
weeks prior to apheresis, with the exception that there is no time restriction if
the volume of bone marrow treated is less than 10% and also the subject has
measurable/evaluable disease outside the radiation port or the site of radiation
has documented progression.
6. Prior CAR Therapy Subjects who have undergone prior CAR therapy must be at least 30
day post CAR infusion and have < 5% of CD3+ cells express the previous CAR if a
validated assay is available.
7. Toxicities due to prior therapy must be stable or resolved (except for clinically non
significant toxicities such as alopecia or cytopenias covered in *footnote to #10)
8. Age greater than or equal to 18 years of age
9. Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2; or
Karnofsky ≥ 60% (See section 13.1, Appendix A)
10. Normal Organ and Marrow Function (supportive care is allowed per institutional
standards, i.e. filgrastim, transfusion)
- ANC ≥ 750/uL*
- Platelet count ≥ 50,000/uL*
- Absolute lymphocyte count (ALC) ≥ 150/uL*
Adequate renal, hepatic, pulmonary and cardiac function defined as:
- Creatinine ≤ 2 mg/dL OR creatinine clearance ≥ 60 mL/min
- Serum ALT/AST ≤ 10x Upper limit of normal (ULN) (Elevated ALT/AST related to
leukemia involvement of the liver will not disqualify a subject).
- Total bilirubin ≤ 1.5 mg/dL, except in subjects with Gilbert's syndrome.
- Cardiac ejection fraction ≥ 45%, no evidence of physiologically significant
pericardial effusion as determined by an ECHO, MUGA or Cardiac MRI [performed
within 180 days or after most recent anthracycline based treatment or mediastinal
radiation therapy (whichever is most recent)]
- No clinically significant ECG findings
- No clinically significant pleural effusion
- Baseline O2 saturation > 92% on room air * ALL subjects will not be excluded
because of pancytopenia ≥ Grade 3 if it is felt by the investigator to be due to
underlying leukemia.
11. CNS Status Subjects with CNS involvement are eligible as long as there are no overt
signs or symptoms that in the evaluation of the investigator would mask or interfere
with the neurological assessment of toxicity.
12. Females of childbearing potential must have a negative serum or urine pregnancy test
within 7 days prior to leukapheresis(females who have undergone surgical sterilization
or who have been postmenopausal for at least 2 years are not considered to be of
childbearing potential)
13. Contraception Subjects 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 (4)
months after receiving the preparative lymphodepletion regimen.
14. Ability to give informed consent. Must be able to give informed consent. Legal
authorized representative (LAR) is permitted if subject is cognitively able to provide
verbal assent.
Exclusion criteria.
1. Recurrent or refractory ALL limited to isolated testicular disease.
2. Hyperleukocytosis (≥ 50,000 blasts/μL) or rapidly progressive disease that in the
estimation of the investigator and sponsor would compromise ability to complete study
therapy.
3. History of other malignancy, unless disease free for at least 3 years. At the
discretion of the Principal Investigator, subjects in remission for 1-2 years prior to
enrollment may be deemed eligible after considering the nature of other malignancy,
likelihood of recurrence during one year following CAR therapy, and impact of prior
treatment on risk of CD22-CAR T cells. Subjects in remission <1 year are not eligible.
- Exception: Nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, bladder,
breast) is eligible.
- Hormonal therapy in subjects in remission > 1 year will be allowed.
4. Presence of active fungal, bacterial, viral, or other infection requiring intravenous
antimicrobials. Simple UTI and uncomplicated bacterial pharyngitis are permitted if
responding to active treatment.
5. No knowledge of:
- HIV,
- Hepatitis B (HBsAg positive) or
- Hepatitis C virus (anti HCV positive) infection. A history of hepatitis B or
hepatitis C is permitted if the viral load is undetectable per quantitative PCR
and/or nucleic acid testing.
6. Presence of cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any
autoimmune disease with CNS involvement that in the judgment of the investigator may
impair the ability to evaluate neurotoxicity.
7. History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or
other clinically significant cardiac disease within 12 months of enrollment.
8. Any medical condition that in the judgement of the sponsor investigator is likely to
interfere with assessment of safety or efficacy of study treatment.
9. History of severe immediate hypersensitivity reaction to any of the agents used in
this study.
10. Women who are pregnant or breastfeeding.
11. In the investigator's judgment, the subject is unlikely to complete all protocol
required study visits or procedures, including follow up visits, or comply with the
study requirements for participation.
12. Primary immunodeficiency or history of autoimmune disease (e.g. Crohns, rheumatoid
arthritis, systemic lupus) requiring systemic immunosuppression/systemic disease
modifying agents within the last 2 years.
