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Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant

ABSTRACT: We report here the design of new antibody-based natural killer cell engager therapeutics (ANKET), single tetraspecific molecules engaging the NK cell activating receptors NKp46 and CD16, the β chain of the interleukin-2 receptor (IL-2R) and a tumor-associated antigen (TAA).

ORGANISM(S): Homo sapiens

PROVIDER: GSE214378 | GEO | 2022/10/05

REPOSITORIES: GEO

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Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant.

Project description:Harnessing innate immunity is emerging as a promising therapeutic approach in cancer. We report here the design of tetraspecific molecules engaging natural killer (NK) cell-activating receptors NKp46 and CD16a, the β-chain of the interleukin-2 receptor (IL-2R), and a tumor-associated antigen (TAA). In vitro, these tetraspecific antibody-based natural killer cell engager therapeutics (ANKETs) induce a preferential activation and proliferation of NK cells, and the binding to the targeted TAA triggers NK cell cytotoxicity and cytokine and chemokine production. In vivo, tetraspecific ANKETs induce NK cell proliferation and their accumulation at the tumor bed, as well as the control of local and disseminated tumors. Treatment of non-human primates with CD20-directed tetraspecific ANKET leads to CD20+ circulating B cell depletion, with minimal systemic cytokine release and no sign of toxicity. Tetraspecific ANKETs, thus, constitute a technological platform for harnessing NK cells as next-generation cancer immunotherapies.

| S-EPMC9589122 | biostudies-literature

Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant

Project description:Antitumor immunity induced by antibody-based natural killer cell engager therapeutics armed with not-alpha IL-2 variant

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EXP2. Antitumor effect MVA-Combo

Project description:RNA-seq analysis of ID8.OVA.Vegf/GFP omental metastases treated intraperitoneally with MVA expressing a tumor-associated antigen (TAA), CD40L and/or CD137L.

2022-07-19 | GSE196024 | GEO

Bispecific dendritic-T Cell Engager potentiates anti-tumor immunity

Project description:Bispecific dendritic-T Cell Engager potentiates anti-tumor immunity

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Bispecific dendritic-T Cell Engager potentiates anti-tumor immunity

Project description:Immune checkpoint inhibition treatment using aPD-1 monoclonal antibodies is a promising cancer immunotherapy approach. However, its effect on tumor immunity is narrow, as most patients do not respond to the treatment or suffer from recurrence. We show that the crosstalk between conventional type I dendritic cells (cDC1) and T cells is essential for an effective aPD-1-mediated anti-tumor response. Accordingly, we developed a Bispecific DC-T Cell Engager (BiCE), a reagent that facilitates physical interactions between PD-1+ T-cells and cDC1. BiCE treatment promoted the formation of active dendritic/T cell crosstalk in the tumor and tumor-draining lymph nodes. In vivo, single cell and physical interacting cell analysis demonstrated the distinct and superior immune reprogramming of the tumors and tumor-draining lymph nodes treated with BiCE, as compared to conventional aPD-1 treatment. BiCE introduces a new concept in immunotherapy, bridging of immune cells to potentiate cell circuits and communication pathways needed for effective anti-tumor immunity.

2024-02-06 | GSE249283 | GEO

Natural killer receptor-positive innate lymphoid cells

Project description:The following lymphocytes were sorted from the lamin propria of the small intestine of EomesGfg/+ RORgtCreTGg Rosa26Yfp/+ by using the markers Lineage- CD45+ Nkp46+ NK1.1+ : 1.convential NK cells (Eomes GFP+ RORgt YFP-) 2. ILC1 (Eomes GFP- RORgt YFP-) 3. exRORgt ILC3 (Eomes GFP- RORgt YFP+). Conventional NK cells from the bone marrow (cNK BM) were sorted from Eomes Gfp/+ mice with the markers Lineage- CD45+ NK1.1+ Eomes GFP+.

2014-04-15 | E-MTAB-2428 | biostudies-arrayexpress

T-cell engager-armed oncolytic vaccinia virus significantly enhances antitumor therapy.

Project description:Oncolytic vaccinia virus (VV) therapy has shown promise in preclinical models and in clinical studies. However, complete responses have rarely been observed. This lack of efficacy is most likely due to suboptimal virus spread through the tumor resulting in limited tumor cell destruction. We reasoned that redirecting T cells to the tumor has the potential to improve the antitumor activity of oncolytic VVs. We, therefore, constructed a VV encoding a secretory bispecific T-cell engager consisting of two single- chain variable fragments specific for CD3 and the tumor cell surface antigen EphA2 (EphA2-T-cell engager-armed VV (EphA2-TEA-VV)). In vitro, EphA2-TEA-VV's ability to replicate and induce oncolysis was similar to that of unmodified virus. However, only tumor cells infected with EphA2-TEA-VV induced T-cell activation as judged by the secretion of interferon-γ and interleukin-2. In coculture assays, EphA2-TEA-VV not only killed infected tumor cells, but in the presence of T cells, it also induced bystander killing of noninfected tumor cells. In vivo, EphA2-TEA-VV plus T cells had potent antitumor activity in comparison with control VV plus T cells in a lung cancer xenograft model. Thus, arming oncolytic VVs with T-cell engagers may represent a promising approach to improve oncolytic virus therapy.

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Trispecific killer engager 161519 enhances natural killer cell function and provides anti-tumor activity against CD19-positive cancers.

Project description:ObjectiveNatural killer (NK) cells have gained considerable attention due to their potential in treating "cold tumors," and are therefore considered as one of the new strategies for curing cancer, by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products.MethodsWe constructed a trispecific killer engager (TriKE) consisting of anti-CD16, IL-15, and anti-CD19. This TriKE was designed to attract CD19+ tumor cells to CD16+ NK cells, whereas IL-15 sustained the proliferation, development, and survival of NK cells.ResultsTreatment with 161519 TriKE in the presence of CD19+ targets upregulated expression of CD69, CD107a, TRAIL, IFN-γ, and TNF-α in NK cells, and significantly improved the proliferation and cytotoxicity of NK cells. NK cells "armed" with 161519 TriKE showed stronger cytolysis against CD19+ targets compared with that of "unarmed" NK cells. A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE, when compared with that in control mice or mice treated with 1619 BiKE. Combined use of IL-2 was a more effective treatment with 1619 BiKE, when compared with that using 161519 TriKE.ConclusionsThe newly generated 161519 TriKE enhanced the proliferation, activation, cytokine secretion, and cytotoxicity of NK cells in the presence of CD19+ tumor cells. The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts, and could be used to treat CD19-positive cancers.

| S-EPMC7721099 | biostudies-literature

A tri-specific killer engager against mesothelin targets NK cells towards lung cancer

Project description:New treatments are required to enhance current therapies for lung cancer. Mesothelin is a surface protein overexpressed in non-small cell lung cancer (NSCLC) that shows promise as an immunotherapeutic target in phase I clinical trials. However, the immunosuppressive environment in NSCLC may limit efficacy of these therapies. We applied time-of-flight mass cytometry to examine the state of circulating mononuclear cells in fourteen patients undergoing treatment for unresectable lung cancer. Six patients had earlier stage NSCLC (I-IVA) and eight had highly advanced NSCLC (IVB). The advanced NSCLC patients relapsed with greater frequency than the earlier stage patients. Before treatment, patients with very advanced NSCLC had a greater proportion of CD14- myeloid cells than patients with earlier NSCLC. These patients also had fewer circulating natural killer (NK) cells bearing an Fc receptor, CD16, which is crucial to antibody-dependent cellular cytotoxicity. We designed a high affinity tri-specific killer engager (TriKE®) to enhance NK cytotoxicity against mesothelin+ targets in this environment. The TriKE consisted of CD16 and mesothelin binding elements linked together by IL-15. TriKE enhanced proliferation of lung cancer patient NK cells in vitro. Lung cancer lines are refractory to NK cell killing, but the TriKE enhanced cytotoxicity and cytokine production by patient NK cells when challenged with tumor. Importantly, TriKE triggered NK cell responses from patients at all stages of disease and treatment, suggesting TriKE can enhance current therapies. These pre-clinical studies suggest mesothelin-targeted TriKE has the potential to overcome the immunosuppressive environment of NSCLC to treat disease.

| S-EPMC9992642 | biostudies-literature

Gene expression profiles of human Natural Killer Cells, unstimulated and stimulated with IPH6501, a tetraspecific NK cell engager (NKCE).

Project description:Gene expression profiles of human Natural Killer Cells, unstimulated and stimulated with IPH6501, a tetraspecific NK cell engager (NKCE).

| PRJNA1143511 | ENA

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