Pilot Study of Redirected Haploidentical Natural Killer Cell Infusions for B-Lineage Acute Lymphoblastic Leukemia

Modern therapy for patients with B-lineage acute lymphoblastic leukemia (ALL) is based on intensive administration of multiple drugs. In patients with relapsed disease, treatment response is generally poor; for most patients, particularly those who relapse while still receiving frontline therapy, the only therapeutic option is hematopoietic stem cell transplantation (HSCT). There is no proven curative therapy for patients who relapse after transplant. Natural killer (NK) cells have powerful anti-leukemia activity. In patients undergoing allogeneic HSCT, several studies have demonstrated NK-mediated anti-leukemic activity. NK cell infusions in patients with leukemia have been shown to be well tolerated and void of graft-versus-host disease (GVHD) effects. NK cell cytotoxicity is most powerful against acute myeloid leukemia (AML) cells, whereas their capacity to lyse ALL cells is generally low. We have developed a novel method to expand and 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 the cell line K562-mb15-41BBL and interleukin (IL)-2. 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 will assess the feasibility, safety and efficacy of infusing expanded, activated redirected NK cells into research participants with B-lineage ALL who have persistent disease after intensive chemotherapy . In this same cohort, we will study the in vivo lifespan and phenotype of these redirected NK cells.

Sex

All

Maximum age

80 Years

Inclusion Criteria:

* NK cell RECIPIENT:

  1. Age: 0 months to 80 years old.
  2. Patients with B-lineage ALL who have persistent disease (0.01% to less than 1% as determined by flow cytometric or molecular measurements of residual disease) despite intensive standard chemotherapy .
  3. Shortening fraction greater than or equal to 25%.
  4. Glomerular filtration rate greater than or equal to 50 ml/min/1.73 m2.
  5. Pulse oximetry greater than or equal to 92% on room air.
  6. Direct bilirubin less than or equal to 3.0 mg/dL (50 mmol/L).
  7. Alanine aminotransferase (ALT) is no more than 2 times the upper limit of normal.
  8. Aspartate transaminases (AST)is no more than 2 times the upper limit of normal.
  9. Karnofsky or Lansky performance score of greater than or equal to 50.
  10. No known allergy to murine products or HAMA testing results within normal limits.
  11. No prior receipt of a gene-transfer agent (e.g. retroviral,adenoviral, lentiviral vector).
  12. Does not have a current pleural or pericardial effusion.
  13. Has a suitable adult family member donor available for NK cell donation.
  14. Has recovered from all acute NCI Common Toxicity Criteria grade II-IV non-hematologic acute toxicities resulting from prior therapy per the judgment of the PI.
  15. At least two weeks since receipt of any biological therapy, systemic chemotherapy, and/or radiation therapy.
  16. Is not receiving more than the equivalent of prednisone 10 mg daily.
  17. Not pregnant (negative serum or urine pregnancy test to be conducted within 7 days prior to enrollment).
  18. Not lactating.
* NK cell DONOR:

  1. First and second relative acceptable.
  2. 18 years of age or above.
  3. Not lactating.
  4. Greater than or equal to 3 of 6 HLA match to recipient.
  5. Meets eligibility and suitability criteria for hematopoietic cells donation as per institutional guidelines.
  6. Not pregnant (negative serum or urine pregnancy test to be conducted within 7 days prior to enrollment).

Exclusion Criteria:

* Failure to meet any of the inclusion criteria.

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• DERIVEDDel Zotto G, Marcenaro E, Vacca P, Sivori S, Pende D, Della Chiesa M, Moretta F, Ingegnere T, Mingari MC, Moretta A, Moretta L. Markers and function of human NK cells in normal and pathological conditions. Cytometry B Clin Cytom. 2017 Mar;92(2):100-114. doi: 10.1002/cyto.b.21508. Epub 2017 Feb 12. PMID 28054442