NK Cell-Based Therapies

Chiossone, Laura; Vivier, Éric

doi:10.1007/978-3-319-62431-0_16

Cited by 2 publications

(3 citation statements)

References 84 publications

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“…We show that redirecting NK cells against cancer targets through binding to NKp46 circumvents the CD64-mediated inhibition of ADCC, with CD123-NKCE active and superior to Fc-engineered ADCC-enhancing IgG1 antibody targeting the same antigen, in vitro, ex vivo and in vivo, whatever the CD64 status of the target cells. Moreover, through their binding to NKp46, CD123-NKCE specifically target NK cells, a population of effector cells with promising perspectives for use in the treatment of cancer [15][16][17][18] , in terms of both efficacy and safety. The efficacy of CD123-NKCE to deplete CD123-positive cells ex vivo from human PBMCs and in vivo in NHP was not associated with the induction of strong cytokine release or clinical signs of toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…NK cell-based therapies may provide new treatment perspectives and a safer alternative for targeting AML cells in this context [15][16][17][18] , without the complications frequently associated with T cell therapies, such as cytokine release syndrome or neurotoxicity 19 . NK cells are innate lymphoid cells that can recognize and kill virus-infected cells or cancer cells [20][21][22] .…”

Section: Cd123-nkce Overcome Cd64-mediated Inhibition Of Aml Killingmentioning

confidence: 99%

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Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123

et al. 2023

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CD123, the alpha chain of the IL-3 receptor, is an attractive target for acute myeloid leukemia (AML) treatment. However, cytotoxic antibodies or T cell engagers targeting CD123 had insufficient efficacy or safety in clinical trials. We show that expression of CD64, the high-affinity receptor for human IgG, on AML blasts confers resistance to anti-CD123 antibody-dependent cell cytotoxicity (ADCC) in vitro. We engineer a trifunctional natural killer cell engager (NKCE) that targets CD123 on AML blasts and NKp46 and CD16a on NK cells (CD123-NKCE). CD123-NKCE has potent antitumor activity against primary AML blasts regardless of CD64 expression and induces NK cell activation and cytokine secretion only in the presence of AML cells. Its antitumor activity in a mouse CD123+ tumor model exceeds that of the benchmark ADCC-enhanced antibody. In nonhuman primates, it had prolonged pharmacodynamic effects, depleting CD123+ cells for more than 10 days with no signs of toxicity and very low inflammatory cytokine induction over a large dose range. These results support clinical development of CD123-NKCE.

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Section: Discussionmentioning

confidence: 99%

Section: Cd123-nkce Overcome Cd64-mediated Inhibition Of Aml Killingmentioning

confidence: 99%

Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123

et al. 2023

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“…NK cells are a diverse population of lymphocytes that contribute both to innate and adaptive immunity against infection, particularly viral infection (42). NK cells also detect and destroy malignant cells (43). In placental reproduction, NK cells perform an essential role in the formation of the placenta (44, 45).…”

Section: Interactions Between Mhc Class I and Nk Cell Receptors Educamentioning

confidence: 99%

Two to Tango: Co-evolution of Hominid Natural Killer Cell Receptors and MHC

2019

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Natural killer (NK) cells have diverse roles in hominid immunity and reproduction. Modulating these functions are the interactions between major histocompatibility complex (MHC) class I molecules that are ligands for two NK cell surface receptor types. Diverse killer cell immunoglobulin-like receptors (KIR) bind specific motifs encoded within the polymorphic MHC class I cell surface glycoproteins, while, in more conserved interactions, CD94:NKG2A receptors recognize MHC-E with bound peptides derived from MHC class I leader sequences. The hominid lineage presents a choreographed co-evolution of KIR with their MHC class I ligands. MHC-A, -B , and -C are present in all great apes with species-specific haplotypic variation in gene content. The Bw4 epitope recognized by lineage II KIR is restricted to MHC-B but also present on some gorilla and human MHC-A. Common to great apes, but rare in humans, are MHC-B possessing a C1 epitope recognized by lineage III KIR. MHC-C arose from duplication of MHC-B and is fixed in all great apes except orangutan, where it exists on approximately 50% of haplotypes and all allotypes are C1-bearing. Recent study showed that gorillas possess yet another intermediate MHC organization compared to humans. Like orangutans, but unlike the Pan-Homo species, duplication of MHC-B occurred. However, MHC-C is fixed, and the MHC-C C2 epitope (absent in orangutans) emerges. The evolution of MHC-C drove expansion of its cognate lineage III KIR. Recently, position −21 of the MHC-B leader sequence has been shown to be critical in determining NK cell educational outcome. In humans, methionine (−21M) results in CD94:NKG2A-focused education whereas threonine (−21T) produces KIR-focused education. This is another dynamic position among hominids. Orangutans have exclusively −21M, consistent with their intermediate stage in lineage III KIR-focused evolution. Gorillas have both −21M and −21T, like humans, but they are unequally encoded by their duplicated B genes. Chimpanzees have near-fixed −21T, indicative of KIR-focused NK education. Harmonious with this observation, chimpanzee KIR exhibit strong binding and, compared to humans, smaller differences between binding levels of activating and inhibitory KIR. Consistent between these MHC-NK cell receptor systems over the course of hominid evolution is the evolution of polymorphism favoring the more novel and dynamic KIR system.

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NK Cell-Based Therapies

Cited by 2 publications

References 84 publications

Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123

Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123

Two to Tango: Co-evolution of Hominid Natural Killer Cell Receptors and MHC

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