Preclinical development of the TLR9 agonist DV281 as an inhaled aerosolized immunotherapeutic for lung cancer: Pharmacological profile in mice, non-human primates, and human primary cells

Kell, Sariah A.; Kachura, Melissa A.; Renn, Alex; Traquina, Paula; Coffman, Robert L.; Campbell, John D.

doi:10.1016/j.intimp.2018.11.019

Cited by 18 publications

(13 citation statements)

References 36 publications

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“…139,145 In preclinical models, lung cancer treatment with aerosolized TLR9 agonist DV281 led to a lung-localized substantial, but transient, cytokine, and chemokine response that was therapeutically beneficial. 146 DV281 is now in a phase 1b/2 study and was proven safe in combination with nivolumab in patients with advanced or metastatic NSCLC. 147 TLR3 agonist poly-ICLC, TLR4 agonist G-100, TLR8 agonist motolimod, and TLR9 agonist SD-101 have proven safe in clinical trials.…”

Section: Pan-reprogramming Of Macrophagesmentioning

confidence: 99%

Macrophage targeting in cancer

Lopez‐Yrigoyen

Cassetta

Pollard

2020

Annals of the New York Academy of Sciences

161

129

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Tumorigenesis is not only determined by the intrinsic properties of cancer cells but also by their interactions with components of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are among the most abundant immune cells in the TME. During initial stages of tumor development, macrophages can either directly promote antitumor responses by killing tumor cells or indirectly recruit and activate other immune cells. As genetic changes occur within the tumor or T helper 2 (T H 2) cells begin to dominate the TME, TAMs begin to exhibit an immunosuppressive protumor phenotype that promotes tumor progression, metastasis, and resistance to therapy. Thus, targeting TAMs has emerged as a strategy for cancer therapy. To date, TAM targeting strategies have focused on macrophage depletion and inhibition of their recruitment into the TME. However, these strategies have shown limited therapeutic efficacy, although trials are still underway with combination therapies. The fact that macrophages have the potential for antitumor activity has moved the TAM targeting field toward the development of TAM-reprogramming strategies to support this antitumor immune response. Here, we discuss the various roles of TAMs in cancer therapy and their immunosuppressive properties, as well as implications for emerging checkpoint inhibitor-based immunotherapies. We review state-of-the-art TAM-targeting strategies, focusing on current ones at the preclinical and clinical trial stages that aim to reprogram TAMs as an oncological therapy.

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Section: Pan-reprogramming Of Macrophagesmentioning

confidence: 99%

Macrophage targeting in cancer

Lopez‐Yrigoyen

Cassetta

Pollard

2020

Annals of the New York Academy of Sciences

161

129

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“…Numerous TLR synthetic ligands have been tested in tumor models and clinical studies, and some were shown to skew TAMs toward an anti-tumoral phenotype. [114][115][116][117][118][119][120] In a melanoma model, local treatment with a TLR7/TLR8 agonist was associated with a modulation of macrophage phenotype that promoted tumor regression. 121,122 Finally, the prototypic cytokine that drives M1-like macrophage polarization, IFNg, was directly used to reprogram macrophages.…”

Section: Reprogramming Immunosuppressive Tams Through Activating Receptorsmentioning

confidence: 99%

Turning enemies into allies—reprogramming tumor-associated macrophages for cancer therapy

Molgora

Colonna

2021

Med

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Checkpoint blockade therapies that target inhibitory receptors on T cells have revolutionized clinical oncology. Antibodies targeting CTLA-4 or the PD-1/PD-1 ligand (PD-L1) axis are now successfully used alone or in combination with chemotherapy for numerous tumor types. Despite the clinical success of checkpoint blockade therapies, tumors exploit multiple mechanisms to escape or subvert the anti-tumor T cell response. Within the tumor microenvironment, tumor-associated macrophages (TAMs) can suppress T cell responses and facilitate tumor growth in various ways, ultimately debilitating clinical responses to T cell checkpoint inhibitors. There is therefore significant interest in identifying biologicals and drugs that target immunosuppressive TAM within the tumor microenvironment and can be combined with immune checkpoint inhibitors. Here, we review approaches that are currently being evaluated to convert immunosuppressive TAM into immunostimulatory macrophages that promote T cell responses and tumor elimination.

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“…Alternative delivery formulations already under clinical evaluation include the VLPformulated TLR9 agonist CMP-001, which improves stability and immunogenicity, and the RIG-I ligand MK-4621 formulated with a transfection reagent to augment cellular uptake. Proofof-principle anti-tumor data with a clinical-grade, aerosolized TLR9 agonist and a nanoparticle-formulated STING agonist represent promising approaches for the treatment of lung cancer with aerosolized delivery (Gallotta et al, 2018;Kell et al, 2019). The precedent for inhaled TLR9 agonists comes from asthma studies, in which TLR9 agonists have been hypothesized to modify T helper subsets.…”

Section: Reviewmentioning

confidence: 99%

Nucleic Acid Sensors as Therapeutic Targets for Human Disease

McWhirter

Jefferies

2020

Immunity

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Innate immune sensors that detect nucleic acids are attractive targets for therapeutic intervention because of their diverse roles in many disease processes. In detecting RNA and DNA from either self or non-self, nucleic acid sensors mediate the pathogenesis of many autoimmune and inflammatory conditions. Despite promising pre-clinical data and investigational use in the clinic, relatively few drugs targeting nucleic acid sensors are approved for therapeutic use. Nevertheless, there is growing appreciation for the untapped potential of nucleic acid sensors as therapeutic targets, driven by the need for better therapies for cancer, infectious diseases, and autoimmune disorders. This review highlights the diverse mechanisms by which nucleic acid sensors are activated and exert their biological effects in the context of various disease settings. We discuss current therapeutic strategies utilizing agonists and antagonists targeting nucleic acid sensors to treat infectious disease, cancer, and autoimmune and inflammatory disorders.

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Preclinical development of the TLR9 agonist DV281 as an inhaled aerosolized immunotherapeutic for lung cancer: Pharmacological profile in mice, non-human primates, and human primary cells

Cited by 18 publications

References 36 publications

Macrophage targeting in cancer

Macrophage targeting in cancer

Turning enemies into allies—reprogramming tumor-associated macrophages for cancer therapy

Nucleic Acid Sensors as Therapeutic Targets for Human Disease

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