Destruction of cancer cells by therapeutic antibodies occurs, at least in part, through antibody-dependent cellular cytotoxicity (ADCC), and this can be mediated by various Fc-receptor-expressing immune cells, including neutrophils. However, the mechanism(s) by which neutrophils kill antibody-opsonized cancer cells has not been established. Here, we demonstrate that neutrophils can exert a mode of destruction of cancer cells, which involves antibody-mediated trogocytosis by neutrophils. Intimately associated with this is an active mechanical disruption of the cancer cell plasma membrane, leading to a lytic (i.e., necrotic) type of cancer cell death. Furthermore, this mode of destruction of antibody-opsonized cancer cells by neutrophils is potentiated by CD47-SIRPα checkpoint blockade. Collectively, these findings show that neutrophil ADCC toward cancer cells occurs by a mechanism of cytotoxicity called trogoptosis, which can be further improved by targeting CD47-SIRPα interactions.

Twenty-three children with nonmalignant disorders received HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) after ex vivo elimination of αβ⁺ T cells and CD19⁺ B cells. The median number of CD34⁺, αβ⁺CD3⁺, and B cells infused was 16.8 × 10⁶, 40 × 10³, and 40 × 10³ cells/kg, respectively. No patient received any posttransplantation pharmacologic prophylaxis for graft-versus-host disease (GVHD). All but 4 patients engrafted, these latter being rescued by a second allograft. Three patients experienced skin-only grade 1 to 2 acute GVHD. No patient developed visceral acute or chronic GVHD. Cumulative incidence of transplantation-related mortality was 9.3%. With a median follow-up of 18 months, 21 of 23 children are alive and disease-free, the 2-year probability of disease-free survival being 91.1%. Recovery of γδ⁺ T cells was prompt, but αβ⁺ T cells progressively ensued over time. Our data suggest that this novel graft manipulation strategy is safe and effective for haplo-HSCT. This trial was registered at www.clinicaltrials.gov as #NCT01810120.

Dendritic cells (DCs) include a heterogeneous family of professional APCs involved in initiation of immunity and in immunologic tolerance. Specifically, peripheral tolerance can be achieved and maintained by promoting regulatory T-cell (Treg) responses and/or T-cell anergy or deletion. Until recently, immature developmental stages of DC differentiation were believed to induce T-cell anergy or Treg cells, whereas DCs transformed into mature DCs by activation stimuli were thought to represent immunogenic DCs capable of inciting primary T-cell responses. This paradigm has been challenged by the demonstration of Treg-cell expansion by antigen-bearing, fully mature DCs. Similarly, semimature DCs with a distinctive interleukin 10 (IL-10)+IL-12- cytokine production profile might be endowed with tolerogenic functions, supporting the concept that DC maturation per se should no longer be considered as a distinguishing feature of immunogenic as opposed to tolerogenic DCs (TDCs). Cytokine-modulated TDCs reflect an incomplete or altered status of monocyte differentiation and promote in vitro induction of Treg cells and/or in vivo protection from autoimmune diseases. Several growth factors, including IL-10, transforming growth factor β (TGF-β), granulocyte colony-stimulating factor (G-CSF), hepatocyte growth factor (HGF), and vasoactive intestinal peptide (VIP), modulate DC maturation and favor the differentiation of TDCs. From a therapeutic standpoint, cytokine-modulated TDCs might be beneficial for prevention and/or treatment of posttransplantation graft-versus-host disease (GVHD) and autoimmunity.

Indoleamine 2,3-dioxygenase (IDO) is a novel immunosuppressive agent expressed in some subsets of normal and neoplastic cells, including acute myeloid leukemia (AML) cells. Here, we show that IDO expression correlates with increased circulating CD4⁺CD25⁺FOXP3⁺ T cells in patients with AML at diagnosis. In vitro, IDO⁺ AML cells increase the number of CD4⁺ CD25⁺ T cells expressing surface CTLA-4 and FOXP3 mRNA, and this effect is completely abrogated by the IDO inhibitor, 1-methyl tryptophan (1-MT). Purified CD4⁺CD25⁺ T cells obtained from coculture with IDO⁺ AML cells act as T regulatory (T_reg) cells because they do not proliferate, do not produce interleukin (IL)–2, and inhibit naive T-cell proliferation. Coculture with IDO⁺AML cells results in the conversion of CD4⁺CD25⁻ into CD4⁺CD25⁺ T cells, which is completely abrogated by 1-MT. Moreover, in mice, intrasplenic injection of IDO⁺ leukemia/lymphoma A20 cells induces the expansion of bona fide T_reg cells by conversion of CD4⁺CD25⁻ T cells; this effect is counteracted by 1-MT treatment. These data indicate that AML cells induce T-cell tolerance by directly converting CD4⁺CD25⁻ T cells into CD4⁺CD25⁺ T_reg cells through an IDO-dependent mechanism.

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.