Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma

Abstract

Summary Multiple myeloma (MM) is a disease with known immune dysregulation. Natural killer (NK) cells have shown preclinical activity in MM. We conducted a first-in-human study of umbilical cord blood-derived (CB) NK cells for MM patients undergoing high dose chemotherapy and autologous haematopoietic stem cell transplantation (auto-HCT). Patients received lenalidomide (10 mg) on days −8 to −2, melphalan 200 mg/m2 on day −7, CB-NK cells on day −5 and auto-HCT on day 0. Twelve patients were enrolled, 3 on each of four CB-NK cell dose levels: 5×106, 1×107, 5×107 and 1×108 CB-NK cells/kg. Ten patients had either high-risk chromosomal changes or a history of relapsed/progressed disease. There were no infusional toxicities and no graft-versus-host disease. One patient failed to engraft due to poor autologous graft quality and was rescued with a back-up autologous graft. Overall, 10 patients achieved at least a very good partial response as their best response, including 8 with near complete response or better. With a median follow-up of 21 months, 4 patients have progressed or relapsed, 2 of whom have died. CB-NK cells were detected in vivo in 6 patients, with an activated phenotype (NKG2D+/NKp30+). These data warrant further development of this novel cellular therapy.

Cellular therapy: Adoptive immunotherapy with expanded natural killer cells

“…These trials have collectively delivered over 300 infusions of expanded and activated NK cells to over 100 patients at doses up to 3 × 10 8 NK cells/kg and demonstrated early evidence of efficacy with no dose‐limiting toxicities. Three Phase I clinical trials have been completed—in patients with multiple myeloma undergoing autologous transplantation (NCT01729091), with AML/MDS receiving haplotransplantation (NCT01904136), and myeloid malignancies undergoing matched allogeneic transplant (NCT01823198, unpublished). A Phase II extension of the haplotransplant trial and two additional Phase I studies (in relapsed/refractory AML [NCT01787474] and pediatric brain tumors [NCT02271711]) are in progress.…”

“…In NCT01729091, 29 patients with multiple myeloma undergoing autologous SCT with melphalan have received lenalidomide and infusions of NK cells expanded from cord blood in doses ranging from 5 × 10 6 to 10 8 /kg. Twelve patients treated during the Phase I dose escalation were reported, in which one patient had graft failure attributable to poor graft quality and there were no toxicities attributed to the NK cell infusions . Results of the Phase II portion of the study have not yet been reported.…”

“…We initially shared the cell line freely for academic use with over 50 investigators worldwide, until several complications with rights and ownership of the cell line precluded further distribution. The original cell line we described (Clone9.mbIL21) proved very effective in propagating NK cells from peripheral blood of normal donors, patients, and cord blood, and a master cell bank (MCB) with full compendial testing for human clinical use was established to generate NK cells for clinical trials …”

NK cell therapy after hematopoietic stem cell transplantation: can we improve anti-tumor effect?

“…In a small study in AML patients with impending relapse, Uharek et al showed favorable two-year survival (40% vs. 11%) when treated with a haploidentical transplantation in combination with post-transplant NK cell infusion, as compared to haploidentical transplantation alone. Also in multiple myeloma patients, NK cell were infused after both autologous and allogeneic transplantation [37,38] with no safety concerns.…”

Conditioning regimens for autologous haematopoietic stem cell transplantation - can natural killer cell therapy help?

“…Initial results of the study reported by Shah et al () merely support the safety of this approach, and in particular, an absence of graft‐versus‐host disease. They also present evidence that circulating NK cells can survive for up to 26 days.…”