Myeloid-Derived Suppressor Cells as Therapeutic Target in Hematological Malignancies

Veirman, Kim De; Valckenborgh, Els Van; Lahmar, Qods; Geeraerts, Xenia; Bruyne, Elke De; Menu, Eline; Riet, Ivan Van; Vanderkerken, Karin; Ginderachter, Jo A. Van

doi:10.3389/fonc.2014.00349

Cited by 85 publications

(73 citation statements)

References 104 publications

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“…The population of PMN-MDSCs is commonly elevated in peripheral blood from patients with many other human cancers, including hematologic malignancies, head and neck, glioma, lung or gastrointestinal cancers. [50, 51] Importantly, TLR9 expression does not seem to be a unique property of prostate cancer-associated PMN-MDSCs and it is observed also in PMN-MDSCs from head and neck cancer patients as verified in our laboratory. (Kortylewski, unpublished data) Therefore, TLR9-targeted delivery can provide a platform technology for immunotherapeutic application in a relatively broad spectrum of human cancers.…”

Section: Cpg-stat3 Inhibitors: Targeting Solid Tumor-associated Myelosupporting

confidence: 64%

Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities

Kortylewski

Moreira

2017

Cancer Immunol Immunother

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Immunotherapies emerged as an alternative for cancer treatment, yet their clinical efficacies are still limited, especially in case of solid tumors. Myeloid immune cells, such as macrophages and myeloid-derived suppressor cells (MDSCs), are often hijacked by tumors and become pivotal inhibitors of antitumor immunity. Immunosuppressive functions of tumor-associated myeloid cells result from the activity of Signal Transducer and Activator of Transcription 3 (STAT3), a transcription factor with well-defined tumorigenic and tolerogenic roles in human cancers. To overcome challenges in the development of pharmacological STAT3 inhibitors, we recently developed oligonucleotide-based strategies for cell-selective, in vivo STAT3 targeting. Conjugation of a STAT3siRNA or decoy STAT3 inhibitors to synthetic Toll-like Receptor 9 (TLR9) agonists, CpG oligonucleotides, allowed for selective delivery into TLR9-positive cells. Cellular targets for CpG-STAT3 inhibitors include non-malignant, tumor-associated myeloid cells, such as polymorphonuclear MDSCs, as well as cancer cells in acute myeloid leukemia, B cell lymphoma and in certain solid tumors. The chemically modified CpG-STAT3 inhibitors resist blood nucleases and thus can be administered intravenously. Their potency relies on the intracellular gain-of-function effect: release of the central immune checkpoint regulator (STAT3) to unleash proinflammatory signaling (CpG/TLR9) in the same antigen-presenting cell. At the cellular level, CpG-STAT3 inhibitors exert two-pronged effect by rescuing T cells from the immune checkpoint control while decreasing survival of cancer cells. In this article, we review the preclinical data on CpG-STAT3 inhibitors and discuss perspectives of using TLR9-targeted delivery of oligonucleotide therapeutics for the generation of novel, more effective and safer cancer immunotherapies.

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Section: Cpg-stat3 Inhibitors: Targeting Solid Tumor-associated Myelosupporting

confidence: 64%

Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities

Kortylewski

Moreira

2017

Cancer Immunol Immunother

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“…Cells of myeloid origin with unique immunosuppressive properties have been found in the blood, spleen, lymphoid tissue and tumor microenvironment in patients with cancer [11–13]. These myeloid-derived suppressor cells (MDSCs) are a heterogenous population of immature myeloid cells that can inhibit T-cell proliferation, cytokine secretion and the recruitment of regulatory T cells.…”

Section: Discussionmentioning

confidence: 99%

Myeloid cells in peripheral blood mononuclear cell concentrates inhibit the expansion of chimeric antigen receptor T cells

et al. 2016

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Background aims Autologous chimeric antigen receptor (CAR) T-cell therapies have shown promising clinical outcomes, but T-cell yields have been variable. CD19- and GD2-CAR T-cell manufacturing records were reviewed to identify sources of variability. Methods CD19-CAR T cells were used to treat 43 patients with acute lymphocytic leukemia or lymphoma and GD2-CAR T cells to treat eight patients with osteosarcoma and three with neuroblastoma. Both types of CAR T cells were manufactured using autologous peripheral blood mononuclear cells (PBMC) concentrates and anti-CD3/CD28 beads for T-cell enrichment and simulation. Results A comparison of the first 6 GD2- and the first 22 CD19-CAR T-cell products manufactured revealed that GD2-CAR T-cell products contained fewer transduced cells than CD19-CAR T-cell products (147 ± 102 × 106 vs 1502 ± 1066 × 106; P = 0.0059), and their PBMC concentrates contained more monocytes (31.4 ± 12.4% vs 18.5 ± 13.7%; P = 0.019). Among the first 28 CD19-CAR T-cell products manufactured, four had poor expansion yielding less than 1 × 106 transduced T cells per kilogram. When PBMC concentrates from these four patients were compared with the 24 others, PBMC concentrates of poorly expanding products contained greater quantities of monocytes (39.8 ± 12.9% vs. 15.3 ± 10.8%, P = 0.0014). Among the patients whose CD19-CAR T cells expanded poorly, manufacturing for two patients was repeated using cryopreserved PBMC concentrates but incorporating a monocyte depleting plastic adherence step, and an adequate dose of CAR T cells was produced for both patients. Conclusions Variability in CAR T-cell expansion is due, at least in part, to the contamination of the starting PBMC concentrates with monocytes.

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“…Much of the data on CAR T cell manufacturing have been generated in patients with ALL or CLL; however, results published in the past 2 years indicate that manufacturing CAR T cell products from patients with high-risk solid tumours might be particularly challenging 19,21 . Reasons for this finding remain under investigation, but one potential explanation relates to the higher quantity of circulating myeloid-derived suppressor cells often found in patients with solid tumours than in those with haematological malignancies 23,24 . Implementation of CAR T cell manufacturing in patients with haematological malignancies beyond B cell leukaemias might also reveal further barriers to successful cell harvesting in certain patient populations and/or disease-specific contexts.…”

mentioning

confidence: 99%

Mechanisms of resistance to CAR T cell therapy

2019

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Myeloid-Derived Suppressor Cells as Therapeutic Target in Hematological Malignancies

Cited by 85 publications

References 104 publications

Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities

Myeloid cells as a target for oligonucleotide therapeutics: turning obstacles into opportunities

Myeloid cells in peripheral blood mononuclear cell concentrates inhibit the expansion of chimeric antigen receptor T cells

Mechanisms of resistance to CAR T cell therapy

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