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

Summary

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.

Timeline

Start

2013-09

Primary completion

2017-02

Completion

2020-02

Outcome

Outcome not reported

Stopped (Business): “Suspended for an interim review of (CAR) CD19 research strategy for the treatment of CD19 positive ALL.”

Publications

• Background Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Blood. 2005 Jul 1;106(1):376-83. doi: 10.1182/blood-2004-12-4797. Epub 2005 Mar 8.
• Background Shimasaki N, Fujisaki H, Cho D, Masselli M, Lockey T, Eldridge P, Leung W, Campana D. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. Cytotherapy. 2012 Aug;14(7):830-40. doi: 10.3109/14653249.2012.671519. Epub 2012 Mar 29.
• Background Fujisaki H, Kakuda H, Shimasaki N, Imai C, Ma J, Lockey T, Eldridge P, Leung WH, Campana D. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res. 2009 May 1;69(9):4010-7. doi: 10.1158/0008-5472.CAN-08-3712. Epub 2009 Apr 21.
• Background Lapteva N, Durett AG, Sun J, Rollins LA, Huye LL, Fang J, Dandekar V, Mei Z, Jackson K, Vera J, Ando J, Ngo MC, Coustan-Smith E, Campana D, Szmania S, Garg T, Moreno-Bost A, Vanrhee F, Gee AP, Rooney CM. Large-scale ex vivo expansion and characterization of natural killer cells for clinical applications. Cytotherapy. 2012 Oct;14(9):1131-43. doi: 10.3109/14653249.2012.700767. Epub 2012 Aug 17.
• Del 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.

Drugs

Indications