Trial watch: STING agonists in cancer therapy.
Ontology highlight
ABSTRACT:
SUBMITTER: Le Naour J
PROVIDER: S-EPMC7466854 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Toll-like receptor 3 (TLR3) is a pattern recognition receptor that senses exogenous (viral) as well as endogenous (mammalian) double-stranded RNA in endosomes. On activation, TLR3 initiates a signal transduction pathway that culminates with the secretion of pro-inflammatory cytokines including type I interferon (IFN). The latter is essential not only for innate immune responses to infection but also for the initiation of antigen-specific immunity against viruses and malignant cells. These aspects of TLR3 biology have supported the development of various agonists for use as stand-alone agents or combined with other therapeutic modalities in cancer patients. Here, we review recent preclinical and clinical advances in the development of TLR3 agonists for oncological disorders.AbbreviationscDC, conventional dendritic cell; CMT, cytokine modulating treatment; CRC, colorectal carcinoma; CTL, cytotoxic T lymphocyte; DC, dendritic cell; dsRNA, double-stranded RNA; FLT3LG, fms-related receptor tyrosine kinase 3 ligand; HNSCC, head and neck squamous cell carcinoma; IFN, interferon; IL, interleukin; ISV, in situ vaccine; MUC1, mucin 1, cell surface associated; PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1; polyA:U, polyadenylic:polyuridylic acid; polyI:C, polyriboinosinic:polyribocytidylic acid; TLR, Toll-like receptor.
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Project description:Toll-like receptors (TLRs) have long been known for their ability to initiate innate immune responses upon exposure to conserved microbial components such as lipopolysaccharide (LPS) and double-stranded RNA. More recently, this family of pattern recognition receptors has been attributed a critical role in the elicitation of anticancer immune responses, raising interest in the development of immunochemotherapeutic regimens based on natural or synthetic TLR agonists. In spite of such an intense wave of preclinical and clinical investigation, only three TLR agonists are currently licensed by FDA for use in cancer patients: bacillus Calmette-Guérin (BCG), an attenuated strain of Mycobacterium bovis that operates as a mixed TLR2/TLR4 agonist; monophosphoryl lipid A (MPL), a derivative of Salmonella minnesota that functions as a potent agonist of TLR4; and imiquimod, a synthetic imidazoquinoline that activates TLR7. One year ago, in the August and September issues of OncoImmunology, we described the main biological features of TLRs and discussed the progress of clinical studies evaluating the safety and therapeutic potential of TLR agonists in cancer patients. Here, we summarize the latest developments in this exciting area of research, focusing on preclinical studies that have been published during the last 13 mo and clinical trials launched in the same period to investigate the antineoplastic activity of TLR agonists.
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Project description:Toll-like receptors (TLRs) are prototypic pattern recognition receptors (PRRs) best known for their ability to activate the innate immune system in response to conserved microbial components such as lipopolysaccharide and double-stranded RNA. Accumulating evidence indicates that the function of TLRs is not restricted to the elicitation of innate immune responses against invading pathogens. TLRs have indeed been shown to participate in tissue repair and injury-induced regeneration as well as in adaptive immune responses against cancer. In particular, TLR4 signaling appears to be required for the efficient processing and cross-presentation of cell-associated tumor antigens by dendritic cells, which de facto underlie optimal therapeutic responses to some anticancer drugs. Thus, TLRs constitute prominent therapeutic targets for the activation/intensification of anticancer immune responses. In line with this notion, long-used preparations such as the Coley toxin (a mixture of killed Streptococcus pyogenes and Serratia marcescens bacteria) and the bacillus Calmette-Guérin (BCG, an attenuated strain of Mycobacterium bovis originally developed as a vaccine against tuberculosis), both of which have been associated with consistent anticancer responses, potently activate TLR2 and TLR4 signaling. Today, besides BCG, only one TLR agonist is FDA-approved for therapeutic use in cancer patients: imiquimod. In this Trial Watch, we will briefly present the role of TLRs in innate and cognate immunity and discuss the progress of clinical studies evaluating the safety and efficacy of experimental TLR agonists as immunostimulatory agents for oncological indications.
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Project description:Toll-like receptors (TLRs) have first been characterized for their capacity to detect conserved microbial components like lipopolysaccharide (LPS) and double-stranded RNA, resulting in the elicitation of potent (innate) immune responses against invading pathogens. More recently, TLRs have also been shown to promote the activation of the cognate immune system against cancer cells. Today, only three TLR agonists are approved by FDA for use in humans: the bacillus Calmette-Guérin (BCG), monophosphoryl lipid A (MPL) and imiquimod. BCG (an attenuated strain of Mycobacterium bovis) is mainly used as a vaccine against tuberculosis, but also for the immunotherapy of in situ bladder carcinoma. MPL (derived from the LPS of Salmonella minnesota) is included in the formulation of Cervarix®, a vaccine against human papillomavirus-16 and -18. Imiquimod (a synthetic imidazoquinoline) is routinely employed for actinic keratosis, superficial basal cell carcinoma, and external genital warts (condylomata acuminata). In this Trial Watch, we will summarize the results of recently completed clinical trials and discuss the progress of ongoing studies that have evaluated/are evaluating FDA-approved TLR agonists as off-label medications for cancer therapy.
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Project description:Accumulating preclinical evidence indicates that Toll-like receptor (TLR) agonists efficiently boost tumor-targeting immune responses (re)initiated by most, if not all, paradigms of anticancer immunotherapy. Moreover, TLR agonists have been successfully employed to ameliorate the efficacy of various chemotherapeutics and targeted anticancer agents, at least in rodent tumor models. So far, only three TLR agonists have been approved by regulatory agencies for use in cancer patients. Moreover, over the past decade, the interest of scientists and clinicians in these immunostimulatory agents has been fluctuating. Here, we summarize recent advances in the preclinical and clinical development of TLR agonists for cancer therapy.
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Project description:During the past 20 years, dozens-if not hundreds-of monoclonal antibodies have been developed and characterized for their capacity to mediate antineoplastic effects, either as they activate/enhance tumor-specific immune responses, either as they interrupt cancer cell-intrinsic signal transduction cascades, either as they specifically delivery toxins to malignant cells or as they block the tumor-stroma interaction. Such an intense research effort has lead to the approval by FDA of no less than 14 distinct molecules for use in humans affected by hematological or solid malignancies. In the inaugural issue of OncoImmunology, we briefly described the scientific rationale behind the use of monoclonal antibodies in cancer therapy and discussed recent, ongoing clinical studies investigating the safety and efficacy of this approach in patients. Here, we summarize the latest developments in this exciting area of clinical research, focusing on high impact studies that have been published during the last 15 months and clinical trials launched in the same period to investigate the therapeutic profile of promising, yet hitherto investigational, monoclonal antibodies.
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Project description:Cardiac glycosides (CGs) are natural compounds sharing the ability to operate as potent inhibitors of the plasma membrane Na+/K+-ATPase, hence promoting-via an indirect mechanism-the intracellular accumulation of Ca2+ ions. In cardiomyocytes, increased intracellular Ca2+ concentrations exert prominent positive inotropic effects, that is, they increase myocardial contractility. Owing to this feature, two CGs, namely digoxin and digitoxin, have extensively been used in the past for the treatment of several cardiac conditions, including distinct types of arrhythmia as well as contractility disorders. Nowadays, digoxin is approved by the FDA and indicated for the treatment of congestive heart failure, atrial fibrillation and atrial flutter with rapid ventricular response, whereas the use of digitoxin has been discontinued in several Western countries. Recently, CGs have been suggested to exert potent antineoplastic effects, notably as they appear to increase the immunogenicity of dying cancer cells. In this Trial Watch, we summarize the mechanisms that underpin the unsuspected anticancer potential of CGs and discuss the progress of clinical studies that have evaluated/are evaluating the safety and efficacy of CGs for oncological indications.
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