CD22-CAR T Cells in Children and Young Adults With B Cell Malignancies

INCLUSION CRITERIA:

   1. Disease Status 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, fluorescence in situ hybridization (FISH), or next generation
      sequencing (NGS) require verification of MRD on two occasions at least 2 weeks
      apart.

      - Subjects with Philadelphia Chromosome positive acute lymphoblastic leukemia
      (Ph+ALL) subjects 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 central nervous system CNS) relapse after
      achieving complete remission (CR).

   Disease Status of lymphoma

      - Histologically confirmed aggressive B cell NHL including the following types
      defined by WHO 2008:

      - DLBCL 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 primary mediastinal (thymic) large B cell lymphoma transformation
      of follicular lymphoma, marginal zone lymphoma or chronic lymphocytic
      leukemia/small lymphocytic lymphoma to DLBCL will also be included

      - Subjects with DLBCL must have progressed, had SD, or recurred after initial
      treatment regimens that include an anthracycline and an anti CD20 monoclonal
      antibody. Subjects with transformed Follicular lymphoma(FL), marginal zone B-cell
      lymphoma (MZL), or chronic lymphocytic leukemia/small lymphocytic lymphoma
      (CLL/SLL) must have progressed, had SD, or recurred with transformed disease
      after initial treatment for DLBCL. Subjects who relapse ≥12 months after therapy
      should have progressed after autologous transplant or been ineligible for
      autologous transplant.

   2. Measureable Disease

      - Subjects with ALL must have evaluable or measurable disease.

      - Subjects with lymphoma: Must have evaluable or measurable disease according to
      the revisedInternational Working. Group( IWG) Response Criteria for Malignant
      Lymphoma. 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 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 subject.

   CD22 expression must be demonstrated subsequent to any anti-CD22 targeted therapy
   (e.g. Moxetumomab pasudotox or inotuzumab ozogamicin) in subjects with ALL

   • Subjects with lymphoma: 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 stem
   cell transplant (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 are at least 100 days post transplant, they have no
   evidence of Graft versus host disease (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.

      - Subjects with ALL may not have receive inotuzumab ozogamicin therapy within the
      past 4 months.

   Exceptions:

      - There is no time restriction with regard to prior intrathecal chemotherapy
      provided there is complete recovery from any acute toxic effects of such;

      - Subjects receiving hydroxyurea may be enrolled provided there has been no
      increase in dose for at least 2 weeks prior to starting apheresis;

      - 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.

      - Subjects receiving steroid therapy at physiologic replacement doses (≤ 5 mg/day
      of prednisone or equivalent doses of other corticosteroids) only are allowed
      provided there has been no increase in dose for at least 2 weeks prior to
      starting apheresis;

      - For radiation therapy: Radiation therapy must have been completed at least 3
      weeks prior to enrollment, 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 will be eligible if at
   least 30 days has elapsed prior to apheresis.

   7. Toxicities from Prior Therapy Toxicities due to prior therapy must be stable (except
   for clinically non significant toxicities such as alopecia)

   8. Age greater than or equal to 1 year and ≤ 30 years of age at time of enrollment. First
   3 subjects treated at the dose level must be at least 16 years old (enrolled on either
   pediatric or adult protocol).

   9. Performance Status:

   Subjects > 10 years of age: Karnofsky ≥ 70% OR Eastern cooperative oncology group
   (ECOG) performance status of 0 or 1; Subjects ≤ 10 years of age: Lansky scale ≥ 70%

10. Normal Organ and Marrow Function (supportive care is allowed per institutional
   standards, i.e. filgrastim, transfusion)

      - Absolute neutrophil count (ANC) ≥ 750/uL*

      - Platelet count ≥ 50,000/uL*

      - Absolute lymphocyte count ≥ 150/uL*

   Adequate renal, hepatic, pulmonary and cardiac function defined as:

      - Creatinine within institutional norms for age (i.e. ≤ 2 mg/dL in adults or
      according to table below in children <18 years) OR creatinine clearance (as
      estimated by Cockcroft Gault Equation) ≥ 60 mL/min Age (Years) Maximum Serum
      Creatinine (mg/dL)

         - 5 Years - Serum Creatinine (mg/dL) = 0.8; 5 < age ≤ 10 Years - Serum
         Creatinine (mg/dL) = 1.0; >10-18 years - Serum Creatinine (mg/dL) = 1.2; >
         18 years - Serum Creatinine (mg/dL) = 2.0

      - Serum (alanine aminotransferase/aspartate aminotransferase(ALT/AST)≤ 10x upper
      limit of normal (ULN) (unless elevated ALT/AST is associated with leukemia
      involvement of the liver, in which case this criterion will be waived and not
      disqualify a patient).

      - 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,

      - No clinically significant ECG findings

      - No clinically significant pleural effusion

      - Baseline oxygen saturation > 92% on room air * 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 ≥ Grade 3 if it is due to disease, based on the results of bone
      marrow studies.

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. Pregnancy Test Females of childbearing potential must have a negative serum or urine
   pregnancy test (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 regimen or for as long as CD19/CD22-CAR T cells
   are detectable in peripheral blood.

14. Ability to give informed consent. All subjects ≥ 18 years of age must be able to give
   informed consent. For subjects <18 years old their legal authorized representative
   (LAR) (i.e. parent or 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. If a minor becomes of age during participation of
   this study, he/she will be asked to reconsent as an adult

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 malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g.
   cervix, bladder, breast) unless disease free for at least 3 years

   4. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or
   requiring IV antimicrobials for management. Simple urinary tract infection (UTI) and
   uncomplicated bacterial pharyngitis are permitted if responding to active treatment.

   5. Ongoing infection with HIV or hepatitis B (HBsAg positive) or hepatitis C virus (anti
   HCV positive) as the immunosuppression contained in this study will pose unacceptable
   risk. A history of hepatitis B or hepatitis C is permitted if the viral load is
   undetectable per quantitative polymerase chain reaction (PCR) and/or nucleic acid
   testing.

   6. CNS disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar
   disease, or any autoimmune disease with CNS involvement hat 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 of child bearing potential who are pregnant or breastfeeding because of the
   potentially dangerous effects of the preparative chemotherapy on the fetus or infant.

11. In the investigators 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. Has 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.