2019
DOI: 10.1080/2162402x.2019.1667743
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Immunogenic cell death in a combined synergic gene- and immune-therapy against cancer

Abstract: It was previously demonstrated that engineered mesenchymal stem cells (MSCs) which express a high level of a very efficient modified gene CYP2B6* (CYP2B6TM-RED) acting as a suicide gene (MSC-2B6*) in combination with cyclophosphamide (CPA) constitute a powerful cell/gene therapy approach for solid tumors. In murine models, this combination led to tumor eradication and triggered a durable immune response against tumoral cells, which prevented recurrence and metastasis.The first goal, in this work, was to determ… Show more

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Cited by 18 publications
(9 citation statements)
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“…However, it appears that TLR4 signaling via MYD88 innate immune signal transduction adaptor (MYD88) [106][107][108] is required and sufficient for cell death to be perceived as immunogenic, as demonstrated with a variety of genetic and pharmacological approaches 16 . In line with this notion, the knockout of HMGB1 in cancer cells and the antibodymediated neutralization of TLR4 in the host limit therapeutically relevant immune responses (and hence disease control) driven by anthracyclines, cyclophosphamide, or oxaliplatin in preclinical in vivo models 103,109 . In addition, loss-of-function polymorphisms in TLR4 have been associated with unfavorable disease outcome in patients with breast cancer receiving anthracyclines as part of their clinical management 103 , in head and neck squamous cell carcinoma patients exposed to standard-of-care chemotherapy 110 , as well as in melanoma patients treated with an experimental DC-based vaccine 111,112 .…”
Section: High-mobility Group Boxmentioning
confidence: 96%
“…However, it appears that TLR4 signaling via MYD88 innate immune signal transduction adaptor (MYD88) [106][107][108] is required and sufficient for cell death to be perceived as immunogenic, as demonstrated with a variety of genetic and pharmacological approaches 16 . In line with this notion, the knockout of HMGB1 in cancer cells and the antibodymediated neutralization of TLR4 in the host limit therapeutically relevant immune responses (and hence disease control) driven by anthracyclines, cyclophosphamide, or oxaliplatin in preclinical in vivo models 103,109 . In addition, loss-of-function polymorphisms in TLR4 have been associated with unfavorable disease outcome in patients with breast cancer receiving anthracyclines as part of their clinical management 103 , in head and neck squamous cell carcinoma patients exposed to standard-of-care chemotherapy 110 , as well as in melanoma patients treated with an experimental DC-based vaccine 111,112 .…”
Section: High-mobility Group Boxmentioning
confidence: 96%
“…This feature might be beneficial in terms of vaccination, but in the context of suicide gene therapy, it might lead to the early removal of CD-expressing cells [23]. Antitumor immunity activation was also observed in the cyclophosphamide GDEPT system [24,25].…”
Section: Gdept: Why Good Intentions Do Not Lead To Paradise In Suicide Cancer Gene Therapymentioning
confidence: 97%
“…This function does not originate from physiological CALR pools within the ER or ERGIC, but from an expanded pool of CALR molecules that are exposed on the membrane of cells undergoing the so-called integrated stress response (ISR), 74 a multipronged, cell-wide reaction to specific perturbations of the extracellular or intracellular microenvironment that cause (in a majority of cases) the loss of ER homeostasis. 75,76 In particular, the translocation of CALR on the outer surface of the plasma membrane, which relies on the inactivating phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (EIF2S1, best known as eIF2α) 77 (Box 2), can be induced by a number of chemotherapeutic agents (i.e., anthracyclines, taxanes, oxaliplatin, bortezomib, PT-112, and others), [78][79][80][81][82][83][84] radiation therapy, 85,86 some variants of photodynamic therapy, [87][88][89][90][91] high hydrostatic pressure, 92,93 oncolytic peptides, [94][95][96] and oncolytic viruses, [97][98][99][100][101] among others. 102,103 Cell surface-exposed CALR delivers potent pro-phagocytic signals to APCs including DCs and their precursors, 104,105 de facto initiating the uptake of dying cells or their corpses in the context of immunostimulation.…”
Section: Calr In Antigen Presentationmentioning
confidence: 99%