The challenges of checkpoint inhibition in the treatment of multiple myeloma

Paul, Barry; Kang, Shuqi; Zheng, Zhihong; Kang, Yubin

doi:10.1016/j.cellimm.2018.10.003

Cited by 16 publications

(12 citation statements)

References 172 publications

(179 reference statements)

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“…Although the development of immune checkpoint inhibitors and advances in nextgeneration sequencing technology have revealed the existence of neoantigens derived from somatic mutations in cancer cells, several types of cancers, including leukaemia, have only a small number of neoantigens, due to rare somatic mutations [15,16]. Multiple myeloma is known to be resistant to ICIs [17], suggesting that there are few neoantigens in this haematological malignancy. Therefore, shared cancer antigens highly expressed in myeloma cells are promising targets in immunotherapies for this disease, including vaccination using cancer-specific peptides [18,19].…”

Section: Discussionmentioning

confidence: 99%

Characteristics of a Novel Target Antigen against Myeloma Cells for Immunotherapy

Matsushita¹,

Saito²,

Yokoe³

et al. 2020

Preprint

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Despite the availability of therapeutic treatments, multiple myeloma is an incurable haematological disorder. In this study, we aimed to clarify the role of CXorf48 as a therapeutic target in multiple myeloma. Based on a previously identified HLA-A*24:02-restiricted epitope from this novel cancer/testis antigen, we characterized the activities of cytotoxic T lymphocytes (CTLs) specific to this antigen against myeloma cells and evaluated the effects of demethylating agents in increasing antigen expression and enhancing the cytotoxic activity of CTLs. CXorf48 expression was examined by RT-PCR using nine myeloma cell lines. Cell lines with low CXorf48 expression were treated by demethylating agents (DMAs), 5-azacytidine (5-aza), and 5-aza-2'-deoxycytidine (DAC) to evaluate gene expression using quantitative RT-PCR. Furthermore, CXorf48-specific CTLs were induced from peripheral blood mononuclear cells of HLA-A*24:02-positive healthy donors to evaluate antigen recognition using ELISpot and 51Cr cytotoxicity assays. CXorf48 was widely expressed in myeloma cells and gene expression was significantly increased by DMAs. Furthermore, CXorf48-specific CTLs recognized DMA-treated myeloma cells. These findings suggest that CXorf48 is a useful target for immunotherapy, such as vaccination, in combination with demethylating agents for the treatment of patients with myeloma.

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Section: Discussionmentioning

confidence: 99%

Characteristics of a Novel Target Antigen against Myeloma Cells for Immunotherapy

Matsushita¹,

Saito²,

Yokoe³

et al. 2020

Preprint

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“…The receptors NKG2D and DNAM-1 are required for NK cell-mediated killing by identifying ligands RAE-1 and PVR expressed on MM cells, respectively ( 74 , 75 ). However, the expression of these receptors decreases on NK cells derived from MM patients, resulting in impairment of NK cell function ( 76 , 77 ). Several studies have suggested that hypoxia decreases NKG2D expression on NK cell surface, partially by hypoxic-tumor-derived micro-vesicles expressing immune modulatory factor TGF-β ( 78 , 79 ).…”

Section: The Impact Of Cellular Metabolic Changes On the Tme And Immumentioning

confidence: 99%

Metabolic Reprogramming Induces Immune Cell Dysfunction in the Tumor Microenvironment of Multiple Myeloma

Kuang

Jin³

et al. 2021

Front. Oncol.

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Tumor cells rewire metabolism to meet their increased nutritional demands, allowing the maintenance of tumor survival, proliferation, and expansion. Enhancement of glycolysis and glutaminolysis is identified in most, if not all cancers, including multiple myeloma (MM), which interacts with a hypoxic, acidic, and nutritionally deficient tumor microenvironment (TME). In this review, we discuss the metabolic changes including generation, depletion or accumulation of metabolites and signaling pathways, as well as their relationship with the TME in MM cells. Moreover, we describe the crosstalk among metabolism, TME, and changing function of immune cells during cancer progression. The overlapping metabolic phenotype between MM and immune cells is discussed. In this sense, targeting metabolism of MM cells is a promising therapeutic approach. We propose that it is important to define the metabolic signatures that may regulate the function of immune cells in TME in order to improve the response to immunotherapy.

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“…Similarly, on KEYNOTE-013 study, Ribrag and colleagues assessed the clinical efficacy of the anti-PD-1 mAb pembrolizumab as single agent in patients with RRMM. No patient of the 30 enrolled in the study experienced any response and the best outcome observed was again disease stabilization (Paul et al, 2018).…”

Section: Immunotherapy In MMmentioning

confidence: 99%

Immunogenic Cell Death and Immunotherapy of Multiple Myeloma

Valle

Anel

Naval

et al. 2019

Front. Cell Dev. Biol.

141

110

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Over the past decades, immunotherapy has demonstrated a prominent clinical efficacy in a wide variety of human tumors. For many years, apoptosis has been considered a non-immunogenic or tolerogenic process whereas necrosis or necroptosis has long been acknowledged to play a key role in inflammation and immune-related processes. However, the new concept of "immunogenic cell death" (ICD) has challenged this traditional view and has granted apoptosis with immunogenic abilities. This paradigm shift offers clear implications in designing novel anti-cancer therapeutic approaches. To date, several screening studies have been carried out to discover bona fide ICD inducers and reveal the inherent capacity of a wide variety of drugs to induce cell death-associated exposure of danger signals and to bring about in vivo anti-cancer immune responses. Recent shreds of evidence place ER stress at the core of all the scenarios where ICD occur. Furthermore, ER stress and the unfolded protein response (UPR) have emerged as important targets in different human cancers. Notably, in multiple myeloma (MM), a lethal plasma cell disorder, the elevated production of immunoglobulins leaves these cells heavily reliant on the survival arm of the UPR. For that reason, drugs that disrupt ER homeostasis and engage ER stress-associated cell death, such as proteasome inhibitors, which are currently used for the treatment of MM, as well as novel ER stressors are intended to be promising therapeutic agents in MM. This not only holds true for their capacity to induce cell death, but also to their potential ability to activate the immunogenic arm of the ER stress response, with the ensuing exposure of danger signals. We provide here an overview of the up-to-date knowledge regarding the cell death mechanisms involved in situations of ER stress with a special focus on the connections with the drug-induced ER stress pathways that evoke ICD. We will also discuss how this could assist in optimizing and developing better immunotherapeutic approaches, especially in MM treatment.

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The challenges of checkpoint inhibition in the treatment of multiple myeloma

Cited by 16 publications

References 172 publications

Characteristics of a Novel Target Antigen against Myeloma Cells for Immunotherapy

Characteristics of a Novel Target Antigen against Myeloma Cells for Immunotherapy

Metabolic Reprogramming Induces Immune Cell Dysfunction in the Tumor Microenvironment of Multiple Myeloma

Immunogenic Cell Death and Immunotherapy of Multiple Myeloma

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