The Next Generation of Pattern Recognition Receptor Agonists: Improving Response Rates in Cancer Immunotherapy

2020 ◽  
Vol 27 (34) ◽  
pp. 5654-5674 ◽  
Author(s):  
Daniel H. O’ Donovan ◽  
Yumeng Mao ◽  
Deanna A. Mele
Keyword(s):  
Pattern Recognition ◽  
Immune System ◽  
Cancer Immunotherapy ◽  
Anticancer Agents ◽  
Adaptive Immune System ◽  
Antitumor Effects ◽  
Tlr Agonists ◽  
Recent Success ◽  
Promising Target ◽  
Tumor Types

The recent success of checkpoint blocking antibodies has sparked a revolution in cancer immunotherapy. Checkpoint inhibition activates the adaptive immune system leading to durable responses across a range of tumor types, although this response is limited to patient populations with pre-existing tumor-infiltrating T cells. Strategies to stimulate the immune system to prime an antitumor response are of intense interest and several groups are now working to develop agents to activate the Pattern Recognition Receptors (PRRs), proteins which detect pathogenic and damageassociated molecules and respond by activating the innate immune response. Although early efforts focused on the Toll-like Receptor (TLR) family of membrane-bound PRRs, TLR activation has been associated with both pro- and antitumor effects. Nonetheless, TLR agonists have been deployed as potential anticancer agents in a range of clinical trials. More recently, the cytosolic PRR Stimulator of IFN Genes (STING) has attracted attention as another promising target for anticancer drug development, with early clinical data beginning to emerge. Besides STING, several other cytosolic PRR targets have likewise captured the interest of the drug discovery community, including the RIG-Ilike Receptors (RLRs) and NOD-like Receptors (NLRs). In this review, we describe the outlook for activators of PRRs as anticancer therapeutic agents and contrast the earlier generation of TLR agonists with the emerging focus on cytosolic PRR activators, both as single agents and in combination with other cancer immunotherapies.

scholarly journals Immune Regulation of Cancer

2010 ◽  
Vol 28 (29) ◽  
pp. 4531-4538 ◽  
Author(s):  
Mary L. Disis
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Adaptive Immune System ◽  
Tumor Stroma ◽  
Tissue Destruction ◽  
Cancer Proliferation ◽  
Patients With Cancer ◽  
Adaptive Immune ◽  
Improved Outcomes ◽  
Tumor Types

Innate and adaptive immune system cells play a major role in regulating the growth of cancer. Although it is commonly thought that an immune response localized to the tumor will inhibit cancer growth, it is clear that some types of inflammation induced in a tumor may also lead to cancer proliferation, invasion, and dissemination. Recent evidence suggests, however, that some patients with cancer can mount an antitumor immune response that has the potential to control or eliminate cancer. Indeed, a so-called “immune response” signature has been described in malignancy that is associated with improved outcomes in several tumor types. Moreover, the presence of specific subsets of T cells, which have the capability to penetrate tumor stroma and infiltrate deep into the parenchyma, identifies patients with an improved prognosis. Immune-based therapies have the potential to modulate the tumor microenvironment by eliciting immune system cells that will initiate acute inflammation that leads to tissue destruction.

Antibody equivalent molecules of the innate immune system: parallels between innate and adaptive immune proteins

2010 ◽  
Vol 16 (3) ◽  
pp. 131-137 ◽  
Author(s):  
Nades Palaniyar
Keyword(s):  
Pattern Recognition ◽  
Immune System ◽  
Innate Immune System ◽  
Adaptive Immune System ◽  
Surfactant Protein ◽  
Innate Immune ◽  
Future Research ◽  
Surfactant Protein D ◽  
Adaptive Immune ◽  
Carbohydrate Arrays

Soluble pattern-recognition innate immune proteins functionally resemble the antibodies of the adaptive immune system. Two major families of such proteins are ficolins and collectins or collagenous lectins (e.g. mannose-binding lectin [MBL], surfactant proteins [SP-A and SP-D] and conglutinin). In general, subunits of ficolins and collectins recognize the carbohydrate arrays of their targets via globular trimeric carbohydrate-recognition domains (CRDs) whereas IgG, IgM and other antibody isotypes recognize proteins via dimeric antigen-binding domains (Fab). Considering the structure and functions of these proteins, ficolins and MBL are analogous to molecules with the complement activating functions of C1q and the target recognition ability of IgG. Although the structure of SP-A is similar to MBL, it does not activate the complement system. Surfactant protein-D and conglutinin could be considered as the collagenous non-complement activating giant IgMs of the innate immune system. Proteins such as peptidoglycan-recognition proteins, pentraxins and agglutinin gp-340/DMBT1 are also pattern-recognition proteins. These proteins may be considered as different isotypes of antibody-like molecules. Proteins such as defensins, cathelicidins and lactoferrins directly or indirectly alter microbes or microbial growth. These proteins may not be considered as antibodies of the innate immune system. Hence, ficolins and collectins could be considered as specialized ‘antibodies of the innate immune system’ instead of ‘ante-antibody’ innate immune molecules. The discovery, structure, functions and future research directions of many of these soluble proteins and receptors such as Toll-like and NOD-like receptors are discussed in this special issue of Innate Immunity.

scholarly journals Persistent anti-heart autoimmunity causes cardiomyocyte damage in chronic heart failure

2019 ◽  
Author(s):  
Amalia Sintou ◽  
Sarah el Rifai ◽  
Catherine Mansfield ◽  
Jose L. Sanchez Alonso ◽  
Stephen M. Rothery ◽  
...  
Keyword(s):  
Heart Failure ◽  
Immune System ◽  
Chronic Heart Failure ◽  
Adaptive Immune System ◽  
Tissue Destruction ◽  
Humoral Factors ◽  
Adaptive Immune ◽  
Promising Target ◽  
Self Tolerance

AbstractAlthough clinicians and researchers have long appreciated the detrimental effects of excessive acute inflammation after myocardial infarction (MI), less is known about the role of the adaptive immune system in MI complications including heart failure. Yet, abundant cardiac self-antigens released from necrotic cardiomyocytes in a highly inflammatory environment are likely to overwhelm peripheral mechanisms of immunological self-tolerance and adaptive auto-reactivity against the heart may cause ongoing tissue destruction and exacerbate progression to chronic heart failure (CHF).Here, we confirm that the adaptive immune system is indeed persistently active in CHF due to ischemic heart disease triggered by MI in rats. Heart draining mediastinal lymph nodes contain active secondary follicles with mature class-switched IgG2a positive cells, and mature anti-heart auto-antibodies binding to cardiac epitopes are still present in serum as late as 16 weeks after MI. When applied to healthy cardiomyocytes in vitro, humoral factors present in CHF serum promoted apoptosis, cytotoxicity and signs of hypertrophy.These findings directly implicate post-MI autoimmunity as an integral feature of CHF progression, constituting a roadblock to effective regeneration and a promising target for therapeutic intervention.

scholarly journals Simple and effective bacterial-based intratumoral cancer immunotherapy

2021 ◽  
Vol 9 (9) ◽  
pp. e002688
Author(s):  
Christina S E Carroll ◽  
Erin R Andrew ◽  
Laeeq Malik ◽  
Kathryn F Elliott ◽  
Moira Brennan ◽  
...  
Keyword(s):  
Immune System ◽  
Tumor Growth ◽  
Cancer Immunotherapy ◽  
Cancer Patients ◽  
Immune Cell ◽  
Human Cancer ◽  
Intratumoral Injection ◽  
Ct Scans ◽  
Antitumor Effects ◽  
Wide Range

BackgroundWe describe intratumoral injection of a slow-release emulsion of killed mycobacteria (complete Freund’s adjuvant (CFA)) in three preclinical species and in human cancer patients.MethodsEfficacy and safety were tested in mammary tumors in mice, in mastocytomas in mice and dogs, and in equine melanomas. In mice, survival, tumor growth, and tumor infiltration by six immune cell subsets (by flow cytometry) were investigated and analyzed using Cox proportional hazards, a random slopes model, and a full factorial model, respectively. Tumor growth and histology were investigated in dogs and horses, as well as survival and tumor immunohistochemistry in dogs. Tumor biopsies were taken from human cancer patients on day 5 (all patients) and day 28 (some patients) of treatment and analyzed by histology. CT scans are provided from one patient.ResultsSignificantly extended survival was observed in mouse P815 and 4T1 tumor models. Complete tumor regressions were observed in all three non-human species (6/186 (3%) of mouse mastocytomas; 3/14 (21%) of canine mastocytomas and 2/11 (18%) of equine melanomas). Evidence of systemic immune responses (regression of non-injected metastases) was also observed. Analysis of immune cells infiltrating mastocytoma tumors in mice showed that early neutrophil infiltration was predictive of treatment benefit. Analysis of the site of mastocytoma regression in dogs weeks or months after treatment demonstrated increased B and T cell infiltrates. Thus, activation of the innate immune system alone may be sufficient for regression of some injected tumors, followed by activation of the acquired immune system which can mediate regression of non-injected metastases. Finally, we report on the use of CFA in 12 human cancer patients. Treatment was well tolerated. CT scans showing tumor regression in a patient with late-stage renal cancer are provided.ConclusionOur data demonstrate that intratumoral injection of CFA has major antitumor effects in a proportion of treated animals and is safe for use in human cancer patients. Further trials in human cancer patients are therefore warranted. Our novel treatment provides a simple and inexpensive cancer immunotherapy, immediately applicable to a wide range of solid tumors, and is suitable to patients in developing countries and advanced care settings.

scholarly journals Defective innate immunity predisposes murine neonates to poor sepsis outcome but is reversed by TLR agonists

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 1750-1758 ◽  
Author(s):  
James L. Wynn ◽  
Philip O. Scumpia ◽  
Robert D. Winfield ◽  
Matthew J. Delano ◽  
Kindra Kelly-Scumpia ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune System ◽  
Adaptive Immune System ◽  
Neutrophil Recruitment ◽  
Polymicrobial Sepsis ◽  
Type I ◽  
Sepsis Mortality ◽  
Tlr Agonists ◽  
Adaptive Immune ◽  
Increased Risk

Abstract Neonates exhibit an increased risk of sepsis mortality compared with adults. We show that in contrast to adults, survival from polymicrobial sepsis in murine neonates does not depend on an intact adaptive immune system and is not improved by T cell–directed adaptive immunotherapy. Furthermore, neonates manifest an attenuated inflammatory and innate response to sepsis, and have functional defects in their peritoneal CD11b+ cells. Activation of innate immunity with either a Toll-like receptor 4 (TLR4) or TLR7/8 agonist, but not a TLR3 agonist, increased the magnitude, but abbreviated the early systemic inflammatory response, reduced bacteremia, and improved survival to polymicrobial sepsis. TLR4 agonist pretreatment enhanced peritoneal neutrophil recruitment with increased oxidative burst production, whereas the TLR7/8 agonist also enhanced peritoneal neutrophil recruitment with increased phagocytic ability. These benefits were independent of the adaptive immune system and type I interferon signaling. Improving innate immune function with select TLR agonists may be a useful strategy to prevent neonatal sepsis mortality.

Developments in anticancer vaccination: budding new adjuvants

2020 ◽  
Vol 401 (4) ◽  
pp. 435-446 ◽  
Author(s):  
Sandra Santos-Sierra
Keyword(s):  
T Cells ◽  
Immune System ◽  
Immune Escape ◽  
Adaptive Immune System ◽  
Cell Detection ◽  
Cancer Vaccination ◽  
Tlr Agonists ◽  
Adaptive Immune ◽  
Anti Cancer ◽  
The Right

AbstractThe immune system has a limited capacity to recognize and fight cells that become cancerous and in cancer patients, the immune system has to seek the right balance between cancer rejection and host-immunosupression. The tumor milieu builds a protective shell and tumor cells rapidly accumulate mutations that promote antigen variability and immune-escape. Therapeutic vaccination of cancer is a promising strategy the success of which depends on a powerful activation of the cells of the adaptive immune system specific for tumor-cell detection and killing (e.g. CD4+ and CD8+ T-cells). In the last decades, the search for novel adjuvants that enhance dendritic cell (DC) function and their ability to prime T-cells has flourished and some Toll-like receptor (TLR) agonists have long been known to be valid immune adjuvants. The implementation of TLR-synthetic agonists in clinical studies of cancer vaccination is replacing the initial use of microbial-derived products with some encouraging results. The purpose of this review is to summarize the latest discoveries of TLR-synthetic agonists with adjuvant potential in anti-cancer vaccination.

scholarly journals Dissolving microneedles delivering cancer cell membrane coated nanoparticles for cancer immunotherapy

RSC Advances ◽  
2021 ◽  
Vol 11 (17) ◽  
pp. 10393-10399
Author(s):  
Wonchan Park ◽  
Keum Yong Seong ◽  
Hye Hyeon Han ◽  
Seung Yun Yang ◽  
Sei Kwang Hahn
Keyword(s):  
Immune System ◽  
Cell Membrane ◽  
Cancer Immunotherapy ◽  
Cancer Cell ◽  
Transdermal Delivery ◽  
Toll Like Receptor ◽  
Tumor Vaccines ◽  
Tlr Agonists ◽  
Coated Nanoparticles ◽  
Dissolving Microneedles

Recently, a variety of tumor vaccines and immune system stimulators such as toll-like receptor (TLR) agonists have been widely investigated for cancer immunotherapy via transdermal delivery.

scholarly journals Immune and Cell Cycle Checkpoint Inhibitors for Cancer Immunotherapy

2021 ◽  
Author(s):  
Erlinda M. Gordon ◽  
Nicole L. Angel ◽  
Ted T. Kim ◽  
Don A. Brigham ◽  
Sant P. Chawla ◽  
...  
Keyword(s):  
Immune System ◽  
Cancer Immunotherapy ◽  
Rational Design ◽  
Checkpoint Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Cancer Surveillance ◽  
Gene Vectors ◽  
Cycle Checkpoint ◽  
Immunosuppressive Tumor Microenvironment ◽  
Tumor Types

The rational design of immunotherapeutic agents has advanced with a fundamental understanding that both innate and adaptive immunity play important roles in cancer surveillance and tumor destruction; given that oncogenesis occurs and cancer progresses through the growth of tumor cells with low immunogenicity in an increasingly immunosuppressive tumor microenvironment. Checkpoint inhibitors in the form of monoclonal antibodies that block cancer’s ability to deactivate and evade the immune system have been widely indicated for a variety of tumor types. Through targeting the biological mechanisms and pathways that cancer cells use to interact with and suppress the immune system, immunotherapeutic agents have achieved success in inhibiting tumor growth while eliciting lesser toxicities, compared to treatments with standard chemotherapy. Development of “precise” bio-active tumor-targeted gene vectors, biotechnologies, and reagents has also advanced. This chapter presents ongoing clinical research involving immune checkpoint inhibitors, while addressing the clinical potential for tumor-targeted gene blockade in combination with tumor-targeted cytokine delivery, in patients with advanced metastatic disease, providing strategic clinical approaches to precision cancer immunotherapy.

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