immunotherapy of cancer
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2022 ◽  
Vol 104 ◽  
pp. 108469
Bo-Jin Chen ◽  
Jing-Wen Zhao ◽  
Da-Hong Zhang ◽  
Ai-Hong Zheng ◽  
Guo-Qing Wu

2022 ◽  
Vol 146 ◽  
pp. 112558
Nafiseh Erfanian ◽  
Afshin Derakhshani ◽  
Saeed Nasseri ◽  
Mohammad Fereidouni ◽  
Behzad Baradaran ◽  

2021 ◽  
Vol 2 (12) ◽  
pp. 100473
Richard E. Beatson ◽  
Ana C. Parente-Pereira ◽  
Leena Halim ◽  
Domenico Cozzetto ◽  
Caroline Hull ◽  

2021 ◽  
Vol 12 ◽  
Mohammed Azharuddin Savanur ◽  
Hadas Weinstein-Marom ◽  
Gideon Gross

Targeting solid tumors with absolute precision is a long-standing challenge in cancer immunotherapy. The identification of antigens, which are expressed by a large fraction of tumors of a given type and, preferably, across various types, but not by normal cells, holds the key to developing safe, off-the-shelf immunotherapies. Although the quest for widely shared, strictly tumor-specific antigens has been the focus of tremendous effort, only few such candidates have been implicated. Almost all antigens that are currently explored as targets for chimeric antigen receptor (CAR) or T cell receptor (TCR)-T cell therapy are also expressed by healthy cells and the risk of on-target off-tumor toxicity has remained a major concern. Recent studies suggest that this risk could be obviated by targeting instead combinations of two or more antigens, which are co-expressed by tumor but not normal cells and, as such, are tumor-specific. Moreover, the expression of a shared tumor antigen along with the lack of a second antigen that is expressed by normal tissues can also be exploited for precise recognition. Additional cues, antigenic or non-antigenic ones, which characterize the tumor microenvironment, could be harnessed to further increase precision. This review focuses on attempts to define the targetable signatures of tumors and assesses different strategies employing advanced synthetic biology for translating such information into safer modes of immunotherapy, implementing the principles of Boolean logic gates.

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A592-A592
Aude De Gassart ◽  
Patrick Brune ◽  
Maelle Mairesse ◽  
Sophie Agaugué ◽  
Ryan Swanson ◽  

Backgroundγ9δ2 T-cells are attractive mediators of cancer immunotherapy due to their strong cytolytic and pro-inflammatory activities and the positive correlation between tumor infiltration and good prognosis [1,2]. ICT01, a novel anti-BTN3A mAb activating γ9δ2 T-cells, is being evaluated in a Phase 1/2a clinical study (NCT04243499)[3,4]. Previous studies have shown that IL-2 (Proleukin®) promotes γ9δ2 T-cells expansion following ICT01 stimulation, which may be clinically useful given that γ9δ2 T-cells are normally <5% of total T-cells [5]. However, the severe toxicity of IL-2 has limited its widespread use. NL-201 is a de novo alpha-independent IL-2/IL-15 agonist that preferentially stimulates CD8 T and NK cell proliferation at low concentrations, enabling a potentially wider therapeutic index than IL-2, and is being evaluated in a Phase 1 clinical study (NCT04659629)[6,7]. Here, we explore the potential of ICT01 and NL-201 to synergistically stimulate the activation and proliferation of γ9δ2 T-cells.MethodsFlow cytometry was used to assess IL-2R signaling (pSTAT5), and γ9δ2 T-cell activation and expansion after in vitro culture of huPBMCs with ICT01, NL201 or the combination. Tumor cell killing activity was monitored upon co-culture of huPBMCs with tumor cell lines (Incucyte). In vivo pharmacology was performed in NCG mice engrafted with 20x106 huPBMCs and treated with ICT01 (1 mg/kg IV)±NL-201 (1, 3 or 10 µg/kg IV). Immune cells were phenotyped by flow cytometry in blood and organs collected at sacrifice (Day 16).ResultsNL-201 is ~100X more potent than IL-2 in triggering IL-2R signaling in γ9δ2 T-cells, without preferential activity on Tregs. NL-201 plus ICT01 induces synergistic expansion of γ9δ2 T-cells, approaching ~50% of T-cells after 8 days versus ~10% with single agents. In addition, the combination of NL-201 and ICT01 promotes γ9δ2 T-cell effector memory differentiation, in contrast to IL-2, which induces primarily central memory phenotype. Importantly, NL-201 enhances ICT01-mediated killing of cancer cells by γ9δ2 T-cells.In mice, a dose-dependent expansion of peripheral γ9δ2 T-cells from ~1–2% at baseline to up to 40% of T-cells was observed in the ICT01+NL-201 combination groups. Consistently, γ9δ2 T-cell number and frequency increase in spleen and lungs of the ICT01+NL-201 treated animals as compared to controls. Expanded γ9δ2 T-cells in the combination groups display an effector memory phenotype, confirming our in vitro results.ConclusionsThese results demonstrate the ability of the ICT01+NL-201 combination to synergistically trigger γ9δ2 T-cell activation, expansion and anti-tumor activity and support clinical evaluation of this combination as a novel therapeutic approach for cancer patients.ReferencesGentles, A. J. et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med 21, 938-945, doi:10.1038/nm.3909 (2015).Tosolini, M. et al. Assessment of tumor-infiltrating TCRVgamma9Vdelta2 gammadelta lymphocyte abundance by deconvolution of human cancers microarrays. Oncoimmunology 6, e1284723, doi:10.1080/2162402X.2017.1284723 (2017).Gassart, A. d. et al. 687 Enhancement of anti-tumor immunity by ICT01: a novel g9d2 T cell-activating antibody targeting butyrophilin-3A (BTN3A). Journal for ImmunoTherapy of Cancer 8, A412-A413, doi:10.1136/jitc-2020-SITC2020.0687 (2020).Marabelle, A. et al. 316 EVICTION Study: Preliminary results in solid tumor patients with ICT01, a first-in-class, gamma9 delta2 T cell activating antibody targeting butyrophilin-3A. Journal for ImmunoTherapy of Cancer 8, A194-A195, doi:10.1136/jitc-2020-SITC2020.0316 (2020).Gassart, A. d. et al. 442 ICT01, an anti-BTN3A mAb that activates Vg9Vd2 T cells, plus interleukin-2: a potent and promising combination for cancer immunotherapy. Journal for ImmunoTherapy of Cancer 8, A268-A269, doi:10.1136/jitc-2020-SITC2020.0442 (2020).Walkey, C., Swanson, R., Ulge, U., Silva Manzano, D. A. & Drachman, J. 576 NL-201, a de novo IL-2 and IL-15 agonist, demonstrates enhanced in vivo antitumor activity in combination with multiple cancer immunotherapies. Journal for ImmunoTherapy of Cancer 8, A346-A346, doi:10.1136/jitc-2020-SITC2020.0576 (2020).Walkey, C. D. et al. Abstract 4518: Pre-clinical development of NL-201: A de novo α-independent IL-2/IL-15 agonist. Cancer Research 80, 4518–4518, doi:10.1158/1538-7445.Am2020-4518 (2020).Ethics ApprovalAll procedures involving animals described in this study have been reviewed and approved by the local ethic committee (CELEAG) and the French Ministry of Research.

2021 ◽  
Vol 6 (4) ◽  
pp. 146-159
A. V. Chetveryakov ◽  
V. L. Tsepelev

The identification of the PD-1 receptor by Tasuku Honjo and CTLA-4 by James Ellison marked the beginning of the study of new regulatory pathways activating the immune response. The term “immune checkpoints” was introduced to denote the system of inhibitory mechanisms that include these proteins. The review presents the literature data on the molecular characteristics of the membrane protein PD-1 (programmed cell death 1 receptor) and its role in the regulation of immunity. We consider the PD-1 pathways used of by tumor cells to escape the immune response. The discovery of immune checkpoints made it possible to develop a new type of targeting therapy for cancer. The review presents the results of clinical trials of drugs that block the interaction between the PD-1 and its ligands in various types of cancer. These drugs include nivolumab, pembrolizumab, and avelumab. Studies of these drugs efficacy in patients with various types of cancer localization were conducted within the CheckMate, KEYNOTE and JAVELIN Solid Tumor programs, with some research being in progress. We analyze the results of studying the clinical efficacy of the drugs in patients with melanoma, lung cancer, renal cell cancer, colorectal cancer, classical Hodgkin’s lymphoma, Merkel carcinoma and stomach cancer. Both positive and inconclusive results in the treatment of patients are noted. These data made it possible to identify promising directions for the use of the drugs in certain localizations of the malignant process, as well as to determine the dose and time of their use to obtain an objective positive response to treatment.

2021 ◽  
Vol 22 (20) ◽  
pp. 11136
Xiaojie Chu ◽  
Zehua Sun ◽  
Du-San Baek ◽  
Wei Li ◽  
John W. Mellors ◽  

Neutrophil elastase (NE) is a serine protease released during neutrophil maturation. High levels of NE are related to lung tissue damage and poor prognosis in cancer; thus, NE is a potential target for therapeutic immunotherapy for multiple lung diseases and cancers. Here, we isolate and characterize two high-affinity, specific, and noncompetitive anti-NE antibodies Fab 1C10 and VH 1D1.43 from two large phage-displayed human Fab and VH libraries. After fusion with human IgG1 Fc, both of them (VH-Fc 1D1.43 and IgG1 1C10) inhibit NE enzymatic activity with VH-Fc 1D1.43 showing comparable inhibitory effects to that of the small molecule NE inhibitor SPCK and IgG1 1C10 exhibiting even higher (2.6-fold) activity than SPCK. Their epitopes, as mapped by peptide arrays combined with structural modeling, indicate different mechanisms for blocking NE activity. Both VH-Fc and IgG1 antibodies block NE uptake by cancer cells and fibroblast differentiation. VH-Fc 1D1.43 and IgG1 1C10 are promising for the antibody-based immunotherapy of cancer and inflammatory diseases.

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