Immunostimulatory nanoparticle incorporating two immune agonists for the treatment of pancreatic tumors

Lorkowski, Morgan; Atukorale, Prabhani U.; Bielecki, Peter; Tong, Kathleen; Covarrubias, Gil; Zhang, Y.; Loutrianakis, Georgia; Moon, Taylor; Santulli, A.R.; Becicka, Wyatt M.; Karathanasis, Efstathios

doi:10.1016/j.jconrel.2020.11.014

Cited by 42 publications

(32 citation statements)

References 54 publications

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“…Conversely, TLR ligation in pancreatic cancer cells has also been linked to tumorigenesis through inflammatory responses that stimulate their anti-apoptotic properties and angiogenesis [129][130][131]. Pre-clinical evidence in PDAC models demonstrated encouraging results of TLR agonist monotherapy [132][133][134] or combined with chemotherapy [135], local tumor eradication (i.e., radiotherapy or ablation) and/or other immunotherapies [136][137][138]. Initial clinical results in PDAC patients are also encouraging.…”

Section: Toll-like Receptor (Tlr) Agonistsmentioning

confidence: 99%

“…Moreover, STING activation augmented costimulatory receptor expression on DCs and converted immune-suppressive macrophages into immune-activating subtypes. Combined with other immunotherapies [138,142,143], or radiotherapy [144], STING agonists in PDAC murine models have demonstrated the ability to induce durable tumor regression and to improve survival. Nonetheless, two initial clinical trials (ClinicalTrials.gov Identifier: NCT03010176; NCT03172936) that employed respectively intratumoral and intravenous STING agonists in patients with solid cancers and lymphomas failed to demonstrate favorable results in terms of tumor regression [145].…”

Section: Stimulator Of Interferon Genes (Sting) Agonistsmentioning

confidence: 99%

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Pancreatic Cancer and Immunotherapy: A Clinical Overview

Timmer

Geboers

Nieuwenhuizen

et al. 2021

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with high mortality. The vast majority of patients present with unresectable, advanced stage disease, for whom standard of care chemo(radio)therapy may improve survival by several months. Immunotherapy has led to a fundamental shift in the treatment of several advanced cancers. However, its efficacy in PDAC in terms of clinical benefit is limited, possibly owing to the immunosuppressive, inaccessible tumor microenvironment. Still, various immunotherapies have demonstrated the capacity to initiate local and systemic immune responses, suggesting an immune potentiating effect. In this review, we address PDAC’s immunosuppressive tumor microenvironment and immune evasion methods and discuss a wide range of immunotherapies, including immunomodulators (i.e., immune checkpoint inhibitors, immune stimulatory agonists, cytokines and adjuvants), oncolytic viruses, adoptive cell therapies (i.e., T cells and natural killer cells) and cancer vaccines. We provide a general introduction to their working mechanism as well as evidence of their clinical efficacy and immune potentiating abilities in PDAC. The key to successful implementation of immunotherapy in this disease may rely on exploitation of synergistic effects between treatment combinations. Accordingly, future treatment approaches should aim to incorporate diverse and novel immunotherapeutic strategies coupled with cytotoxic drugs and/or local ablative treatment, targeting a wide array of tumor-induced immune escape mechanisms.

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Section: Toll-like Receptor (Tlr) Agonistsmentioning

confidence: 99%

Section: Stimulator Of Interferon Genes (Sting) Agonistsmentioning

confidence: 99%

Pancreatic Cancer and Immunotherapy: A Clinical Overview

Timmer

Geboers

Nieuwenhuizen

et al. 2021

Cancers

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“…We specically measured the hyperthermia-induced elimination of tumor-promoting immune cells. Considering that the majority of nanoparticles are oen taken up by immune cells in the TME rather than by cancer cells, [19][20][21] IONP-induced hyperthermia can decrease the levels of these inhibitory immune cells or ideally completely deplete them. We chose to test this concept using the murine 4T1 model of triple-negative breast cancer, which contains large numbers of dysfunctional immune cells, many of which possess an immunosuppressive phenotype.…”

Section: Introductionmentioning

confidence: 99%

Hyperthermia-mediated changes in the tumor immune microenvironment using iron oxide nanoparticles

et al. 2021

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“…This augmentation would be expected to improve tumor infiltrating B cell content and GC formation within the TLS + TME, conceivably improving immune-mediated control of tumor growth. Indeed, several recent reports support therapeutic synergy using treatment regimens combining STING agonists and TLR1/2 agonist Pam3Csk ( 97 ), TLR4 agonist monophosphoryl lipid A ( 102 ), TLR7/8 agonist MEDI9197 ( 103 ) or TLR9 agonist CpG ( 104 ). Although the impact of these interventional protocols on TLS formation within the TME and the evolving anti-tumor immune response remains unknown, these aspects are expected to be actively pursued in future studies.…”

Section: Combination Sting Agonist Therapies May Be Required To Promote the Neogenesis Of Classical Mature Tls In The Tmementioning

confidence: 99%

STINGing the Tumor Microenvironment to Promote Therapeutic Tertiary Lymphoid Structure Development

et al. 2021

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Tertiary lymphoid structures (TLS), also known as ectopic lymphoid structures (ELS) or tertiary lymphoid organs (TLO), represent a unique subset of lymphoid tissues noted for their architectural similarity to lymph nodes, but which conditionally form in peripheral tissues in a milieu of sustained inflammation. TLS serve as regional sites for induction and expansion of the host B and T cell repertoires via an operational paradigm involving mature dendritic cells (DC) and specialized endothelial cells (i.e. high endothelial venules; HEV) in a process directed by TLS-associated cytokines and chemokines. Recent clinical correlations have been reported for the presence of TLS within tumor biopsies with overall patient survival and responsiveness to interventional immunotherapy. Hence, therapeutic strategies to conditionally reinforce TLS formation within the tumor microenvironment (TME) via the targeting of DC, vascular endothelial cells (VEC) and local cytokine/chemokine profiles are actively being developed and tested in translational tumor models and early phase clinical trials. In this regard, a subset of agents that promote tumor vascular normalization (VN) have been observed to coordinately support the development of a pro-inflammatory TME, maturation of DC and VEC, local production of TLS-inducing cytokines and chemokines, and therapeutic TLS formation. This mini-review will focus on STING agonists, which were originally developed as anti-angiogenic agents, but which have recently been shown to be effective in promoting VN and TLS formation within the therapeutic TME. Future application of these drugs in combination immunotherapy approaches for greater therapeutic efficacy is further discussed.

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Immunostimulatory nanoparticle incorporating two immune agonists for the treatment of pancreatic tumors

Cited by 42 publications

References 54 publications

Pancreatic Cancer and Immunotherapy: A Clinical Overview

Pancreatic Cancer and Immunotherapy: A Clinical Overview

Hyperthermia-mediated changes in the tumor immune microenvironment using iron oxide nanoparticles

STINGing the Tumor Microenvironment to Promote Therapeutic Tertiary Lymphoid Structure Development

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