Exploiting Natural Killer cell engagers to control pediatric B-cell precursor acute lymphoblastic leukemia
Menée à l'aide de lignées cellulaires, d'échantillons sanguins et d'échantillons de moelle osseuse, cette étude met en évidence l'efficacité d'engageurs de cellules NK pour traiter une leucémie lymphoblastique aiguë à cellules précurseurs de lymphocytes B
Natural killer (NK) cells represent a promising cell type in antitumor immunotherapy for efficacy and safety, particularly in the treatment of hematological malignancies. NK cells have been shown to exert anti-leukemia activity in the context of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Recent products have been developed to boost the activation of NK cells only when cross-linked by tumor cells, avoiding any off-target effect. Here, we tested the in vitro effect of different NK cell engagers (NKCEs), which trigger either NKp46 or NKp30 together with CD16A, and target either CD19 or CD20 to induce killing of pediatric B cell precursor acute lymphoblastic leukemia (BCP-ALL). Target cells were NALM-16 and MHH-CALL-4 cell lines and four primary leukemia, while effector cells were resting NK cells derived from healthy donors and pediatric leukemia patients after αβT/B-depleted haplo-HSCT. The NK-resistant MHH-CALL-4 was efficiently killed through all NKCEs. Boosting of NK activity against MHH-CALL-4 was documented also by degranulation and IFN-γ production. Due to the lack of CD20 and high expression of CD19 on primary BCP-ALL, we focused on NKCEs targeting CD19. NKp46- and NKp30-based NKCEs displayed similar potency in inducing NK cell activity, even when challenged with primary BCP-ALL blasts. Remarkably, their efficacy was shown also using NK cells derived from transplanted patients. NKCE-induced activation against BCP-ALL can override the HLA-specific inhibitory interactions, although the strongest response was observed by the alloreactive NK cell subset. These data strongly support the therapeutic use of NKp46/CD16A/CD19-NKCE to fight refractory/relapsed leukemia in pre- or post-transplantation settings.