In the mix: the potential benefits of adding GM-CSF to CpG-B in the local treatment of patients with early-stage melanoma

Koster, Bas D.; Jong, Tamarah D. de; Hout, Mari F.C.M. van den; Sluijter, Berbel J.R.; Vuylsteke, Ronald J.C.L.M.; Molenkamp, Barbara G.; Vosslamber, Saskia; Tol, M.P. van den; Eertwegh, Alfons J.M. van den; Gruijl, Tanja D. de

doi:10.1080/2162402x.2019.1708066

Cited by 6 publications

(7 citation statements)

References 32 publications

(43 reference statements)

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“…Local administration of ICI has been described in pre-clinical models and tested in several types of cancer in clinical trials by us and others, with positive results (42,(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70). We reported that peritumoral delivery of anti-CTLA-4 in mouse models resulted in an equally efficient antitumor response as observed after systemic administration, without the usually associated inflammatory side effects (65).…”

Section: In Conclusion: the Rise Of Local Immunotherapymentioning

confidence: 79%

Immunotherapy Goes Local: The Central Role of Lymph Nodes in Driving Tumor Infiltration and Efficacy

et al. 2021

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Immune checkpoint blockade (ICB) has changed the therapeutic landscape of oncology but its impact is limited by primary or secondary resistance. ICB resistance has been related to a lack of T cells infiltrating into the tumor. Strategies to overcome this hurdle have so far focused on the tumor microenvironment, but have mostly overlooked the role of tumor-draining lymph nodes (TDLN). Whereas for CTLA-4 blockade TDLN have long since been implicated due to its perceived mechanism-of-action involving T cell priming, only recently has evidence been emerging showing TDLN to be vital for the efficacy of PD-1 blockade as well. TDLN are targeted by developing tumors to create an immune suppressed pre-metastatic niche which can lead to priming of dysfunctional antitumor T cells. In this review, we will discuss the evidence that therapeutic targeting of TDLN may ensure sufficient antitumor T cell activation and subsequent tumor infiltration to facilitate effective ICB. Indeed, waves of tumor-specific, proliferating stem cell-like, or progenitor exhausted T cells, either newly primed or reinvigorated in TDLN, are vital for PD-1 blockade efficacy. Both tumor-derived migratory dendritic cell (DC) subsets and DC subsets residing in TDLN, and an interplay between them, have been implicated in the induction of these T cells, their imprinting for homing and subsequent tumor control. We propose that therapeutic approaches, involving local delivery of immune modulatory agents for optimal access to TDLN, aimed at overcoming hampered DC activation, will enable ICB by promoting T cell recruitment to the tumor, both in early and in advanced stages of cancer.

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Section: In Conclusion: the Rise Of Local Immunotherapymentioning

confidence: 79%

Immunotherapy Goes Local: The Central Role of Lymph Nodes in Driving Tumor Infiltration and Efficacy

et al. 2021

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“…112 Corroborating initial findings, the intratumoral or systemic administration of DMXAA or other STING agonists, alone or combined with other therapeutic agents, have ultimately been attributed pronounced therapeutic effects in numerous murine models of fibrosarcoma, glioma, 80 melanoma, 66,113 as well as breast, 114-117 colorectal 118 and prostate carcinoma. 119 Moreover, various CDNs have been shown to boost the therapeutic activity of anticancer vaccines in a variety of tumor models, including (1) mouse 4T1 triple-negative mammary carcinomas treated with a Listeria monocytogenes-based vaccine; [120][121][122] (2) mouse B16 melanomas treated with the TRIVAX vaccine, which consists of synthetic peptides, the Tolllike receptor 3 (TLR3) agonist polyinosinic:polycytidylic acid (polyI:C) 123 and co-stimulatory antibodies 124,125 targeting CD40, 126 or the STINGVAX vaccine, a cellular vaccine engineered to secrete colony-stimulating factor 2 (CSF2, best known as GM-CSF), 127 plus an immune checkpoint blocker targeting programmed cell death 1 (PDCD1, best known as PD-1), [128][129][130] and (3) mouse CT26 colorectal carcinoma treated with the STINGVAX vaccine plus a PD-1 blocker. 128,130 However, natural CDNs are rapidly degraded by circulating and cell-bound enzymes, including ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), 131 calling for the development of molecules with improved stability for clinical applications.…”

Section: Sting Signaling In Preclinical Tumor Modelsmentioning

confidence: 99%

Trial watch: STING agonists in cancer therapy

et al. 2020

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Stimulator of interferon response cGAMP interactor 1 (STING1, best known as STING) is an endoplasmic reticulum-sessile protein that serves as a signaling hub, receiving input from several pattern recognition receptors, most of which sense ectopic DNA species in the cytosol. In particular, STING ensures the production of type I interferon (IFN) in response to invading DNA viruses, bacterial pathogens, as well as DNA leaking from mitochondria or the nucleus (e.g., in cells exposed to chemotherapy or radiotherapy). As a type I IFN is critical for the initiation of anticancer immune responses, the pharmaceutical industry has generated molecules that directly activate STING for use in oncological indications. Such STING agonists are being tested in clinical trials with the rationale of activating STING in tumor cells or tumor-infiltrating immune cells (including dendritic cells) to elicit immunostimulatory effects, alone or in combination with a range of established chemotherapeutic and immunotherapeutic regimens. In this Trial Watch, we discuss preclinical evidence and accumulating clinical experience shaping the design of Phase I and Phase II trials that evaluate the safety and preliminary efficacy of STING agonists in cancer patients.

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“…Total RNA was isolated from PBMC and reverse transcribed as previously described. 18 Forty-seven type I IFN response genes (IRGs) were selected based on significant upregulation in more than three experiments published on the Interferome database ( http://www.interferome.org/ ). Custom-designed TaqMan assays for each IRG were supplied by Applied Biosystems.…”

Section: Methodsmentioning

confidence: 99%

T cell infiltration on local CpG-B delivery in early-stage melanoma is predominantly related to CLEC9A⁺CD141⁺cDC1 and CD14⁺antigen-presenting cell recruitment

Koster

González

Hout

et al. 2021

J Immunother Cancer

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BackgroundWe previously reported CpG-B injection at the primary tumor excision site prior to re-excision and sentinel node biopsy to result in immune activation of the sentinel lymph node (SLN), increased melanoma-specific CD8+ T cell rates in peripheral blood, and prolonged recurrence-free survival. Here, we assessed recruitment and activation of antigen-presenting cell (APC) subsets in the SLN and at the injection site in relation to T cell infiltration.MethodsRe-excision skin specimens from patients with clinical stage I-II melanoma, collected 7 days after intradermal injection of either saline (n=10) or 8 mg CpG-B (CPG7909, n=12), were examined by immunohistochemistry, quantifying immune subsets in the epidermis, papillary, and reticular dermis. Counts were related to flow cytometric data from matched SLN samples. Additional in vitro cultures and transcriptional analyses on peripheral blood mononuclear cells (PBMCs) were performed to ascertain CpG-induced APC activation and chemokine profiles.ResultsSignificant increases in CD83+, CD14+, CD68+, and CD123+ APC were observed in the reticular dermis of CpG-B-injected skin samples. Fluorescent double/triple staining revealed recruitment of both CD123+BDCA2+ plasmacytoid dendritic cells (DCs) and BDCA3/CD141+CLEC9A+ type-1 conventional DC (cDC1), of which only the cDC1 showed considerable levels of CD83 expression. Simultaneous CpG-B-induced increases in T cell infiltration were strongly correlated with both cDC1 and CD14 counts. Moreover, cDC1 and CD14+ APC rates in the reticular dermis and matched SLN suspensions were positively correlated. Flow cytometric, transcriptional, and chemokine release analyses of PBMC, on in vitro or in vivo exposure to CpG-B, indicate a role for the activation and recruitment of both cDC1 and CD14+ monocyte-derived APCs in the release of CXCL10 and subsequent T cell infiltration.ConclusionThe CpG-B-induced concerted recruitment of cDC1 and CD14+ APC to the injection site and its draining lymph nodes may allow for both the (cross-)priming of T cells and their subsequent homing to effector sites.

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In the mix: the potential benefits of adding GM-CSF to CpG-B in the local treatment of patients with early-stage melanoma

Cited by 6 publications

References 32 publications

Immunotherapy Goes Local: The Central Role of Lymph Nodes in Driving Tumor Infiltration and Efficacy

Immunotherapy Goes Local: The Central Role of Lymph Nodes in Driving Tumor Infiltration and Efficacy

Trial watch: STING agonists in cancer therapy

T cell infiltration on local CpG-B delivery in early-stage melanoma is predominantly related to CLEC9A⁺CD141⁺cDC1 and CD14⁺antigen-presenting cell recruitment

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In the mix: the potential benefits of adding GM-CSF to CpG-B in the local treatment of patients with early-stage melanoma

Cited by 6 publications

References 32 publications

Immunotherapy Goes Local: The Central Role of Lymph Nodes in Driving Tumor Infiltration and Efficacy

Immunotherapy Goes Local: The Central Role of Lymph Nodes in Driving Tumor Infiltration and Efficacy

Trial watch: STING agonists in cancer therapy

T cell infiltration on local CpG-B delivery in early-stage melanoma is predominantly related to CLEC9A+CD141+cDC1 and CD14+antigen-presenting cell recruitment

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T cell infiltration on local CpG-B delivery in early-stage melanoma is predominantly related to CLEC9A⁺CD141⁺cDC1 and CD14⁺antigen-presenting cell recruitment