Induction of tumor regression by intratumoral STING agonists combined with anti–programmed death‐L1 blocking antibody in a preclinical squamous cell carcinoma model

Gadkaree, Shekhar K.; Fu, Juan; Sen, Rupashree; Korrer, Michael; Allen, Clint; Kim, Young Jin

doi:10.1002/hed.24704

Cited by 43 publications

(35 citation statements)

References 32 publications

(65 reference statements)

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“…injection into B16.F10 tumors was enhanced when combined with anti-programmed death-1 (PD-1) and anti-cytotoxic T-lymphocyte associated-4 (CTLA-4) antibodies ( 55 ). In other studies, CDNs together with anti-PD-1 incited much stronger antitumor effects than monotherapy in a mouse model of squamous cell carcinoma model as well of melanoma ( 59 , 60 ). Luo et al showed great synergy by combining a STING-activating nanovaccine and an anti-PD1 antibody, and suggested generation of long-term antitumor memory in TC-1 tumor model ( 61 ).…”

Section: Preclinical Evaluation Of Sting Agonists For Cancer Treatmenmentioning

confidence: 84%

Targeting Cytosolic Nucleic Acid-Sensing Pathways for Cancer Immunotherapies

2018

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The innate immune system provides the first line of defense against pathogen infection though also influences pathways involved in cancer immunosurveillance. The innate immune system relies on a limited set of germ line-encoded sensors termed pattern recognition receptors (PRRs), signaling proteins and immune response factors. Cytosolic receptors mediate recognition of danger damage-associated molecular patterns (DAMPs) signals. Once activated, these sensors trigger multiple signaling cascades, converging on the production of type I interferons and proinflammatory cytokines. Recent studies revealed that PRRs respond to nucleic acids (NA) released by dying, damaged, cancer cells, as danger DAMPs signals, and presence of signaling proteins across cancer types suggests that these signaling mechanisms may be involved in cancer biology. DAMPs play important roles in shaping adaptive immune responses through the activation of innate immune cells and immunological response to danger DAMPs signals is crucial for the host response to cancer and tumor rejection. Furthermore, PRRs mediate the response to NA in several vaccination strategies, including DNA immunization. As route of double-strand DNA intracellular entry, DNA immunization leads to expression of key components of cytosolic NA-sensing pathways. The involvement of NA-sensing mechanisms in the antitumor response makes these pathways attractive drug targets. Natural and synthetic agonists of NA-sensing pathways can trigger cell death in malignant cells, recruit immune cells, such as DCs, CD8+ T cells, and NK cells, into the tumor microenvironment and are being explored as promising adjuvants in cancer immunotherapies. In this minireview, we discuss how cGAS–STING and RIG-I–MAVS pathways have been targeted for cancer treatment in preclinical translational researches. In addition, we present a targeted selection of recent clinical trials employing agonists of cytosolic NA-sensing pathways showing how these pathways are currently being targeted for clinical application in oncology.

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Section: Preclinical Evaluation Of Sting Agonists For Cancer Treatmenmentioning

confidence: 84%

Targeting Cytosolic Nucleic Acid-Sensing Pathways for Cancer Immunotherapies

2018

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“…Indeed, the synergistic combination of RR-CDG (i.t., every 3 days) with a PD-L1 blockade (i.p.,100 μg) stimulated stronger antitumor responses than monotherapy in a head and neck squamous cell cancer (HNSCC) mouse model [149]. Intramuscular (i.m.)…”

Section: Indirect Sting Agonistsmentioning

confidence: 99%

Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy

et al. 2020

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Cellular recognition of microbial DNA is an evolutionarily conserved mechanism by which the innate immune system detects pathogens. Cyclic GMP-AMP synthase (cGAS) and its downstream effector, stimulator of interferon genes (STING), are involved in mediating fundamental innate antimicrobial immunity by promoting the release of type I interferons (IFNs) and other inflammatory cytokines. Accumulating evidence suggests that the activation of the cGAS-STING axis is critical for antitumor immunity. The downstream cytokines regulated by cGAS-STING, especially type I IFNs, serve as bridges connecting innate immunity with adaptive immunity. Accordingly, a growing number of studies have focused on the synthesis and screening of STING pathway agonists. However, chronic STING activation may lead to a protumor phenotype in certain malignancies. Hence, the cGAS-STING signaling pathway must be orchestrated properly when STING agonists are used alone or in combination. In this review, we discuss the dichotomous roles of the cGAS-STING pathway in tumor development and the latest advances in the use of STING agonists.

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“…Moreover, a synergistic effect was seen when ADUS100 was combined with an anti-PD-1 antibody and an OX-40 agonist antibody where tumor clearance was seen in 40% of the mice compared to only 10% of the mice with ADUS100 treatment ( 128 ). STING agonists also showed increased tumor regression when combined with anti-PD1 antibody in a pre-clinical squamous cell carcinoma model ( 129 ). Based on the success in pre-clinical models, multiple clinical trials are ongoing to test STING agonist monotherapy or in combination with anti-PD1 antibodies (NCT03010176, NCT03172936).…”

Section: Targeting Type I Ifn Signaling Pathway As a Promising Stratementioning

confidence: 99%

Plasticity of Type I Interferon-Mediated Responses in Cancer Therapy: From Anti-tumor Immunity to Resistance

2018

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The efficacy of several therapeutic strategies against cancer, including cytotoxic drugs, radiotherapy, targeted immunotherapies and oncolytic viruses, depend on intact type I interferon (IFN) signaling for the promotion of both direct (tumor cell inhibition) and indirect (anti-tumor immune responses) effects. Malfunctions of this pathway in tumor cells or in immune cells may be responsible for the lack of response or resistance. Although type I IFN signaling is required to trigger anti-tumor immunity, emerging evidence indicates that chronic activation of type I IFN pathway may be involved in mediating resistance to different cancer treatments. The plastic and dynamic features of type I IFN responses should be carefully considered to fully exploit the therapeutic potential of strategies targeting IFN signaling. Here, we review available evidence supporting the involvement of type I IFN signaling in mediating resistance to various cancer therapies and highlight the most promising modalities that are being tested to overcome resistance.

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Induction of tumor regression by intratumoral STING agonists combined with anti–programmed death‐L1 blocking antibody in a preclinical squamous cell carcinoma model

Abstract: This study demonstrates the antitumor effects of CDNs in a HNSCC cell line. These preclinical data strongly support the future clinical development of intratumoral CDN in patients with HNSCC. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1086-1094, 2017.

Cited by 43 publications

References 32 publications

Targeting Cytosolic Nucleic Acid-Sensing Pathways for Cancer Immunotherapies

Targeting Cytosolic Nucleic Acid-Sensing Pathways for Cancer Immunotherapies

Comprehensive elaboration of the cGAS-STING signaling axis in cancer development and immunotherapy

Plasticity of Type I Interferon-Mediated Responses in Cancer Therapy: From Anti-tumor Immunity to Resistance

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