Exploiting Natural Killer Cell Engagers to Control Pediatric B-cell Precursor Acute Lymphoblastic Leukemia

Natalia Colomar-Carando (1, 2) , Laurent Gauthier (3) , Pietro Merli (4) , Fabrizio Loiacono (1) , Paolo Canevali (1) , Michela Falco (5) , Federica Galaverna (4) , Benjamin Rossi (3) , Frédéric Bosco (3) , Mélody Caratini (3) , Maria Cristina Mingari (1, 2) , Franco Locatelli (4, 6) , Eric Vivier (7, 3, 8) , Raffaella Meazza (1) , Daniela Pende (1)

1 IRCCS Ospedale Policlinico San Martino [Genoa, Italy]
2 UniGe - Università degli studi di Genova = University of Genoa
3 Innate Pharma
4 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
5 IRCCS Istituto Giannina Gaslini [Genoa, Italy]
6 UNIROMA - Università degli Studi di Roma "La Sapienza" = Sapienza University [Rome]
7 CIML - Centre d'Immunologie de Marseille - Luminy
8 TIMONE - Hôpital de la Timone [CHU - APHM]

◥ Natural killer (NK) cells represent a promising cell type in antitumor immunotherapy for efficacy and safety, particularly in the treatment of hematologic malignancies. NK cells have been shown to exert antileukemia activity in the context of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). 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 (NKCE), 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 leukemias, while effector cells were resting NK cells derived from healthy donors and pediatric patients with leukemia after abT/B-depleted haplo-HSCT. The NK cell-resistant MHH-CALL-4 was efficiently killed using all NKCEs. Boosting of NK activity against MHH-CALL-4 was also evident by degranulation and IFNg production. Because of 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 at inducing NK-cell activity, even when challenged with primary BCP-ALL blasts. Their efficacy was shown also using NK cells derived from transplanted patients. NKCE-induced activation against BCP-ALL can override HLA-specific inhibitory interactions, although the strongest response was observed by the alloreactive NK-cell subset. These data support the therapeutic use of NKp46/CD16A/ CD19-NKCE to fight refractory/relapsed leukemia in pretransplantation or posttransplantation settings.

Domaines: Sciences du Vivant [q-bio]

Natalia Colomar-Carando, Laurent Gauthier, Pietro Merli, Fabrizio Loiacono, Paolo Canevali, et al.. Exploiting Natural Killer Cell Engagers to Control Pediatric B-cell Precursor Acute Lymphoblastic Leukemia. Cancer Immunology Research, 2022, 10, pp.291 - 302. ⟨10.1158/2326-6066.cir-21-0843⟩. ⟨hal-03952692⟩