ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancer

Ye, Wenda; Gunti, Sreenivasulu; Allen, Clint; Hong, Youji; Clavijo, Paúl E.; Waes, Carter Van; Schmitt, Nicole C.

doi:10.1080/2162402x.2019.1710398

Cited by 33 publications

(32 citation statements)

References 61 publications

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“…An in vivo vaccination assay was used to confirm the role of tolinapant as a novel immunogenic cell death (ICD) inducer. 30,31 Subcutaneous implantation of BW5147 cells killed in vitro by tolinapant in the presence of TNF-a completely protected immunocompetent AKR/J mice against rechallenge with live BW5147 tumor cells when injected 1 week later into the opposite flank (Figure 6D). This effect was comparable to a positive control, in which BW5147 cells killed by mitoxantrone, a known inducer of ICD, 32,33 were used.…”

Section: Tolinapant Promotes Antigen-specific Responses Via Induction Of Necroptosis In An In Vivo Model Of T-cell Lymphomamentioning

confidence: 99%

Antagonism of inhibitors of apoptosis proteins reveals a novel, immune response-based therapeutic approach for T-cell lymphoma

et al. 2021

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Tolinapant (ASTX660) is a potent, non-peptidomimetic antagonist of cIAP1/2 and XIAP, which is currently being evaluated in a phase 2 study in T-cell lymphoma (TCL) patients. Tolinapant has demonstrated evidence of single agent clinical activity in relapsed/refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). To investigate the mechanism of action underlying the single agent activity observed in the clinic we have used a comprehensive translational approach integrating in vitro and in vivo models of T-cell lymphoma confirmed by data from human tumor biopsies. Here we show that tolinapant acts as an efficacious immunomodulatory molecule capable of inducing complete tumor regression in a syngeneic model of TCL exclusively in the presence of an intact immune system. These findings were confirmed in samples from our ongoing clinical study showing that tolinapant treatment can induce changes in gene expression and cytokine profile consistent with immune modulation. Mechanistically, we show that tolinapant can activate both the adaptive and the innate arms of the immune system through the induction of immunogenic forms of cell death. In summary, we describe a novel role for IAP antagonists as immunomodulatory molecules capable of promoting a robust anti-tumor immune response in TCL.

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Section: Tolinapant Promotes Antigen-specific Responses Via Induction Of Necroptosis In An In Vivo Model Of T-cell Lymphomamentioning

confidence: 99%

Antagonism of inhibitors of apoptosis proteins reveals a novel, immune response-based therapeutic approach for T-cell lymphoma

et al. 2021

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“…In line with this notion, accumulating preclinical and clinical evidence indicates that various DAMPs and DAMPassociated processes may have prognostic and predictive value for patients affected by a variety of tumors 45 . Moreover, there is ample evidence that treatment-driven ICD can elicit anticancer immune responses that reinforce the therapeutic effects of conventional anticancer chemotherapies and radiotherapy [46][47][48][49] . So far, however, only a few bona fide ICD inducers have been successfully employed in the clinic as therapeutics (Table 1) 46,50 .…”

Section: Introductionmentioning

confidence: 99%

Detection of immunogenic cell death and its relevance for cancer therapy

et al. 2020

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Chemotherapy, radiation therapy, as well as targeted anticancer agents can induce clinically relevant tumor-targeting immune responses, which critically rely on the antigenicity of malignant cells and their capacity to generate adjuvant signals. In particular, immunogenic cell death (ICD) is accompanied by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which altogether confer a robust adjuvanticity to dying cancer cells, as they favor the recruitment and activation of antigen-presenting cells. ICD-associated DAMPs include surface-exposed calreticulin (CALR) as well as secreted ATP, annexin A1 (ANXA1), type I interferon, and high-mobility group box 1 (HMGB1). Additional hallmarks of ICD encompass the phosphorylation of eukaryotic translation initiation factor 2 subunit-α (EIF2S1, better known as eIF2α), the activation of autophagy, and a global arrest in transcription and translation. Here, we outline methodological approaches for measuring ICD markers in vitro and ex vivo for the discovery of next-generation antineoplastic agents, the development of personalized anticancer regimens, and the identification of optimal therapeutic combinations for the clinical management of cancer.

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“…In in vivo experiments, ASTX660 heightened IR-induced ICD modestly to inhibit tumor generation in 72% of mice in contrast with 50% of mice treated with IR alone. In addition, ASTX660 combined with IR promoted clonal expansion of TIL by enhancing DCs activation and MHC I expression ( 73 ).…”

Section: The Methods Of Enhancing Ir-induced Icdmentioning

confidence: 99%

Immunogenic Cell Death Induction by Ionizing Radiation

et al. 2021

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Immunogenic cell death (ICD) is a form of regulated cell death (RCD) induced by various stresses and produces antitumor immunity via damage-associated molecular patterns (DAMPs) release or exposure, mainly including high mobility group box 1 (HMGB1), calreticulin (CRT), adenosine triphosphate (ATP), and heat shock proteins (HSPs). Emerging evidence has suggested that ionizing radiation (IR) can induce ICD, and the dose, type, and fractionation of irradiation influence the induction of ICD. At present, IR-induced ICD is mainly verified in vitro in mice and there is few clinical evidence about it. To boost the induction of ICD by IR, some strategies have shown synergy with IR to enhance antitumor immune response, such as hyperthermia, nanoparticles, and chemotherapy. In this review, we focus on the molecular mechanisms of ICD, ICD-promoting factors associated with irradiation, the clinical evidence of ICD, and immunogenic forms of cell death. Finally, we summarize various methods of improving ICD induced by IR.

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ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancer

Abstract: (2020) ASTX660, an antagonist of cIAP1/2 and XIAP, increases antigen processing machinery and can enhance radiation-induced immunogenic cell death in preclinical models of head and neck cancer, OncoImmunology, 9:1, 1710398,

Cited by 33 publications

References 61 publications

Antagonism of inhibitors of apoptosis proteins reveals a novel, immune response-based therapeutic approach for T-cell lymphoma

Antagonism of inhibitors of apoptosis proteins reveals a novel, immune response-based therapeutic approach for T-cell lymphoma

Detection of immunogenic cell death and its relevance for cancer therapy

Immunogenic Cell Death Induction by Ionizing Radiation

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