Intratumoural immunotherapy: activation of nucleic acid sensing pattern recognition receptors

Agrawal, Sudhir; Kandimalla, Ekambar R.

doi:10.1016/j.iotech.2019.10.001

Cited by 14 publications

(15 citation statements)

References 141 publications

(203 reference statements)

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“…The activation of the STimulator of INterferon Genes (STING) pathway increases IFN-β production by tumor-resident DCs and induces the recruitment and priming of T cells against tumor antigens ( 218 ). The discovery of agonists of STING in mice [5,6-dimethyllxanthenone-4-acetic acid or DMXAA ( 219 , 220 )] and humans [MIW815/ADU-S100 and MK-1454 synthetic cyclic dinucleotides or small molecules like GSK3745417 ( 221 , 222 )] extended the possibilities of rational combinations with ICIs. Until the development of small-molecules suitable for systemic administration ( 223 ), clinical trials with the first STING agonists were focused on intratumoral delivery and thus limited to patients with accessible tumors.…”

Section: Combination Strategies For Improving Ici Therapy By Targetinmentioning

confidence: 99%

Myeloid Cells as Clinical Biomarkers for Immune Checkpoint Blockade

et al. 2020

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Immune checkpoint inhibitors are becoming standard treatments in several cancer types, profoundly changing the prognosis of a fraction of patients. Currently, many efforts are being made to predict responders and to understand how to overcome resistance in non-responders. Given the crucial role of myeloid cells as modulators of T effector cell function in tumors, it is essential to understand their impact on the clinical outcome of immune checkpoint blockade and on the mechanisms of immune evasion. In this review we focus on the existing clinical evidence of the relation between the presence of myeloid cell subsets and the response to anti-PD(L)1 and anti-CTLA-4 treatment. We highlight how circulating and tumor-infiltrating myeloid populations can be used as predictive biomarkers for immune checkpoint inhibitors in different human cancers, both at baseline and on treatment. Moreover, we propose to follow the dynamics of myeloid cells during immunotherapy as pharmacodynamic biomarkers. Finally, we provide an overview of the current strategies tested in the clinic that use myeloid cell targeting together with immune checkpoint blockade with the aim of uncovering the most promising approaches for effective combinations.

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Section: Combination Strategies For Improving Ici Therapy By Targetinmentioning

confidence: 99%

Myeloid Cells as Clinical Biomarkers for Immune Checkpoint Blockade

et al. 2020

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“…Activating innate immune signaling in cancer cells, such as by intratumoral injection of ligands, is currently proposed to be an interesting strategy to combat cancer cells and is expected to be applied concomitantly with immune checkpoint inhibitors [6,7]. The group of receptors involved in activating innate immune signaling are called pattern recognition receptors (PRRs), which include Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs).…”

Section: Introductionmentioning

confidence: 99%

Anti‐pyroptotic function of TGF‐β is suppressed by a synthetic dsRNA analogue in triple negative breast cancer cells

et al. 2021

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Development of innovative therapeutic modalities would address an unmet clinical need in the treatment of triple negative breast cancer (TNBC). Activation of retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) such as melanoma differentiation-associated gene 5 (MDA5) and RIG-I in cancer cells is suggested to suppress tumor progression by inducing cell death. Transfection of polyI:C, a conventionally used synthetic double-stranded RNA (dsRNA) analogue that activates RLRs, has been evaluated in clinical trials. However, detailed mechanisms of tumor suppression by RLRs, especially interactions with other signaling pathways, remain elusive. Here, we showed that transfection of polyI:C suppressed transforming growth factor-b (TGF-b) signaling in a MDA5-and RIG-I-dependent manner. We found that suppression of TGF-b signaling by polyI:C promoted cancer cell death, which was attenuated by forced expression of constitutively active Smad3. More detailed analysis suggested that cell death by polyI:C transfection exhibited characteristics of pyroptosis, which is distinct from apoptosis. Therapeutic efficacy of polyI:C transfection was also demonstrated using a mouse model. These results indicated that intratumor administration of polyI:C and related dsRNA analogues may be promising treatments for TNBC through inhibition of the anti-pyroptotic function of TGF-b.

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“…10,46 The efficacy of TLR9 agonists with ICI therapy has been investigated in preclinical studies and is currently being tested in clinical trials; and represent a promising therapeutic strategy to overcome ICI resistance, particularly for T cell uninflamed tumors. 47,48 In this review article, we describe TLR9 receptor distribution and function, describe TLR9 signaling and delineate the role of TLR9 agonists in cancer immunotherapy with a focus on ongoing clinical trials.…”

Section: Introductionmentioning

confidence: 99%

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

Karapetyan

Luke

Davar

2020

OTT

102

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Toll-like receptor 9 (TLR9) is a pattern recognition receptor that is predominantly located intracellularly in immune cells, including dendritic cells, macrophages, natural killer cells, and other antigen-presenting cells (APC). The primary ligands for TLR9 receptors are unmethylated cytidine phosphate guanosine (CpG) oligodinucleotides (ODN). TLR9 agonists induce inflammatory processes that result in the enhanced uptake and killing of microorganisms and cancer cells as well as the generation of adaptive immune responses. Preclinical studies of TLR9 agonists suggested efficacy both as monotherapy and in combination with several agents, which led to clinical trials in patients with advanced cancer. In these studies, intravenous, intratumoral, and subcutaneous routes of administration have been tested; with anti-tumor responses in both treated and untreated metastatic sites. TLR9 agonist monotherapy is safe, although efficacy is minimal in advanced cancer patients; conversely, combinations appear to be more promising. Several ongoing phase I and II clinical trials are evaluating TLR9 agonists in combination with a variety of agents including chemotherapy, radiotherapy, targeted therapy, and immunotherapy agents. In this review article, we describe the distribution, structure and signaling of TLR9; discuss the results of preclinical studies of TLR9 agonists; and review ongoing clinical trials of TLR9 agonists singly and in combination in patients with advanced solid tumors.

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Intratumoural immunotherapy: activation of nucleic acid sensing pattern recognition receptors

Cited by 14 publications

References 141 publications

Myeloid Cells as Clinical Biomarkers for Immune Checkpoint Blockade

Myeloid Cells as Clinical Biomarkers for Immune Checkpoint Blockade

Anti‐pyroptotic function of TGF‐β is suppressed by a synthetic dsRNA analogue in triple negative breast cancer cells

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

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