Genetically Modified Haploidentical Natural Killer Cell Infusions for B-Lineage Acute Lymphoblastic Leukemia

NK cell cytotoxicity is most powerful against acute myeloid leukemia (AML) cells, whereas
their capacity to lyse ALL cells is generally low and difficult to predict. A novel method
has been developed to redirect NK cells towards CD19, a molecule highly expressed on the
surface of B-lineage ALL cells, but not expressed on normal cells other than B-lymphocytes.
In this method, donor NK cells are first expanded by co-culture with irradiated K562 cell
line modified to express membrane bound IL-15 and 41BB ligand (K562-mb15-41BBL).
Overexpansion of these proteins promotes selective growth of NK cells. Then, the expanded NK
cells are transduced with a signaling receptor that binds to CD19 (anti-CD19-BB-zeta). NK
cells expressing these receptors showed powerful anti-leukemic activity against CD19+ ALL
cells in vitro and in an animal model of leukemia.

This study represents the translation of laboratory findings into clinical application. It
will allow us to assess the safety of infusing genetically modified NK cells into research
participants who have chemotherapy refractory or relapse B-lineage ALL. In this same
cohort, we also intend to study the in vivo lifespan and phenotype of genetically modified
NK cells and explore the efficacy of NK cells in patients with B-lineage ALL.

Inclusion Criteria:

- Age: less than or equal to 18 years of age. May be greater than 18 years of age if
currently a St. Jude patient.

- Patients with relapsed or refractory B-lineage ALL who are not eligible for
hematopoietic stem cell transplantation (HSCT) because their leukemia is not in
remission (>5% blasts in bone marrow as evidenced either by morphology or by flow
cytometry).

- Shortening fraction greater than or equal to 25%.

- Glomerular filtration rate greater than or equal to 50 cc/min/1.73 m2.

- Pulse oximetry greater than or equal to 92% on room air.

- Direct bilirubin less than or equal to 3.0 mg/dL.

- Alanine aminotransferase (ALT) is no more than 2 times the upper limit of normal.

- Aspartate transaminases (AST) is no more than 2 times the upper limit of normal.

- Karnofsky or Lansky performance score of greater than or equal to 50.

- No known allergy to murine products or HAMA testing results within normal limits.

- No prior receipt of a gene-transfer agent (e.g. retroviral, adenoviral, lentiviral
vector).

- Does not have a current pleural or pericardial effusion.

- Has a suitable adult family member donor available for NK cell donation.

- Has recovered from all acute NCI Common Toxicity Criteria grade II-IV non-hematologic
acute toxicities resulting from previous therapy as per the judgment of the principal
investigator.

- At least two weeks since receipt of any biological therapy, systemic chemotherapy,
and/or radiation therapy.

- Is not receiving more than the equivalent of prednisone 10 mg daily.

Exclusion Criteria:

- Pregnant (negative serum or urine pregnancy test to be conducted within 7 days prior
to enrollment)

- Breastfeeding