Infusion of Host-Derived Unlicensed NK Cells Improves Donor Engraftment in Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is an efficacious and frequently the only treatment option for some hematological malignances. However, it often faces severe morbidities and/or mortalities due to graft versus host disease, and the severity of the conditioning regiment needed, that result in toxicity-related issues poorly tolerable for some patients. These shortcomings have led to the development of less aggressive alternatives like non-myeloablative (NMAC) or reduced-intensity conditioning regiments (RIC). However, these approaches tend to have an increase of cancer relapse and limited persistence of donor-specific chimerism. Thus, strategies that lead towards an accelerated and more durable donor engraftment are still needed. Here, we took advantage of the ability of host-derived unlicensed NK (UnLicNK) cells to favor donor cell engraftment during myeloablative allo-HCT, and evaluated if the adoptive transfer of this cell type can improve donor chimerism in NAMC settings. Indeed, the infusion of these cells significantly increased mixed chimerism in a sublethal allo-HCT mouse model, resulting in a more sustainable donor cell engraftment when compared to the administration of licensed NK cells or HCT controls. We observed an overall increase in the total number and proportion of donor B, NK and myeloid cells after UnLicNK cell infusion. Additionally, the extension and durability of donor chimerism was similar to the one obtained after the tolerogenic Tregs infusion. These results serve as the needed bases for the implementation of the adoptive transfer of UnLicNK cells to upgrade NMAC protocols and enhance allogeneic engraftment during HCT.

Statins act as transient type I interferon inhibitors to enable the antitumor activity of modified vaccinia Ankara viral vectors

“…Single-cell suspension of the indicated organs collected at the indicated times were stained as previously described. 26 Fluorescence minus one or biological comparison controls were used for cell analysis. 27 The following antibodies were used and acquired from BioLegend (San Diego, California, USA): PE anti-mouse IFNAR1 (MAR1-5A3), PE Mouse IgG 1 (MOPC-21), Zombie NIR, Brilliant Violet 650 anti-mouse CD19 (6D5), Brilliant Violet 510 anti-mouse CD45 (30-F11), Brilliant Violet 605 anti-mouse TCR β chain (H57-597), PERCPCy5.5 CD44 (IM7), APC CD62L (MEL-14), AF700 Ki67 (16A8), PE-Dazzel 594 Tim3 (B8.2C12), BV785 PD1 (29F.1A12), 7-AAD Viability Staining Solution.…”

Prospects and Advances in Adoptive Natural Killer Cell Therapy for Unmet Therapeutic Needs in Pediatric Bone Sarcomas

“…Pérez-Martinez et al, subsequently studied this allogeneic therapy in solid tumors, showing encouraging results with all of their patients presenting some type of clinical response (complete response in 3 patients, partial response in 2 patients and stable disease in 1 patient after 9 months of follow-up) [156]. The disadvantages of this source is the risk of alloreactivity and multiple invasive procedures that might be required [157]. Due to the limited amount of NK cells in peripheral blood, several leukapheresis procedures and, in some instances, a central intravenous line might be required to obtain the necessary volume of blood, increasing the risk of complications for the donor [158].…”