Phase 1 clinical trial using mbIL21 ex vivo–expanded donor-derived NK cells after haploidentical transplantation

Abstract

Relapse has emerged as the most important cause of treatment failure after allogeneic hematopoietic stem cell transplantation (HSCT). To test the hypothesis that natural killer (NK) cells can decrease the risk of leukemia relapse, we initiated a phase 1 dose-escalation study of membrane-bound interleukin 21 (mbIL21) expanded donor NK cells infused before and after haploidentical HSCT for high-risk myeloid malignancies. The goals were to determine the safety, feasibility, and maximum tolerated dose. Patients received a melphalan-based reduced-intensity conditioning regimen and posttransplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis. NK cells were infused on days -2, +7, and +28 posttransplant. All NK expansions achieved the required cell number, and 11 of 13 patients enrolled received all 3 planned NK-cell doses (1 × 10/kg to 1 × 10/kg per dose). No infusional reactions or dose-limiting toxicities occurred. All patients engrafted with donor cells. Seven patients (54%) developed grade 1-2 acute GVHD (aGVHD), none developed grade 3-4 aGVHD or chronic GVHD, and a low incidence of viral complications was observed. One patient died of nonrelapse mortality; 1 patient relapsed. All others were alive and in remission at last follow-up (median, 14.7 months). NK-cell reconstitution was quantitatively, phenotypically, and functionally superior compared with a similar group of patients not receiving NK cells. In conclusion, this trial demonstrated production feasibility and safety of infusing high doses of ex vivo-expanded NK cells after haploidentical HSCT without adverse effects, increased GVHD, or higher mortality, and was associated with significantly improved NK-cell number and function, lower viral infections, and low relapse rate posttransplant.

PD-L1 blockade enhances anti-tumor efficacy of NK cells

“…18 In this study, FC21-NK cells were given before and after stem cell transplant and resulted in decreased relapse rate as well as lower occurrence of post-transplant viral reactivation and graft- versus -host disease. Peripheral blood taken from treated patients on day 30 post-SCT (21 days after 2 NK cell infusions) was analyzed for NK and T cell content, phenotype and function.…”

“…NK cells have shown to be very effective in preventing relapse in residual disease setting, under low tumor burden. 18,42 In several trials testing efficacy of haploidentical NK cells in patients with advanced relapsed or refractory tumors, responses were observed only in a small subgroup of patients and were hampered by co-expansion of Tregs which were thought to be of patient origin. 43-46 Our results suggest that expansion of Tregs may arise in the tumor microenvironment upon PD-L1 expression, and can even occur by expansion from the very small amount of T cells transferred as part of an adoptive NK cell product.…”

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

“…We recently reported on a phase I clinical study in highrisk myeloid leukemia patients treated with haploidentical transplants and multiple donor-derived, ex vivo expanded NK cell infusions using feeder cells expressing mbIL-21 [13]. In this dose escalation study, three doses of NK cells infused on Day-2, + 7 and + 28 (up to Day + 90), up to 1 × 10 8 /kg were safely infused without reaching a maximum tolerated dose and with no induction of grade 3 or 4 acute GvHD or higher TRM.…”

“…This association is true for both allogeneic and autologous transplantation [14][15][16][17]. Although the NK cells are about the first cells that can be detected in the peripheral blood after transplantation, their phenotype and function are immature [13]. It takes at least 3-6 months until these cells gain KIR expression and become functionally active to induce optimal anti-leukemia responses.…”

“…While Symons and colleagues showed that recipients of an inhibitory KIR-genemismatched graft had lower relapse rate and improved survival and that patients with KIR Bx donor for recipients with homozygous A haplotype had improved non-relapse mortality and survival [10], Hosokai et al reported that KIR Bx donors for recipients with A/A haplotype had higher incidence of acute GVHD with no impact on non-relapse mortality, relapse or survival [11]. Low NK cell numbers and function early after transplantation have been observed related to the PTCy administration [12,13], while higher numbers of NK cells have been associated with better transplant outcomes [8][9][10][11]. This association is true for both allogeneic and autologous transplantation [14][15][16][17].…”