Trial Watch

Abstract

Toll-like receptors (TLRs) are an evolutionarily conserved group of enzymatically inactive, single membrane-spanning proteins that recognize a wide panel of exogenous and endogenous danger signals. Besides constituting a crucial component of the innate immune response to bacterial and viral pathogens, TLRs appear to play a major role in anticancer immunosurveillance. In line with this notion, several natural and synthetic TLR ligands have been intensively investigated for their ability to boost tumor-targeting immune responses elicited by a variety of immunotherapeutic and chemotherapeutic interventions. Three of these agents are currently approved by the US Food and Drug Administration (FDA) or equivalent regulatory agencies for use in cancer patients: the so-called bacillus Calmette-Guérin, monophosphoryl lipid A, and imiquimod. However, the number of clinical trials testing the therapeutic potential of both FDA-approved and experimental TLR agonists in cancer patients is stably decreasing, suggesting that drug developers and oncologists are refocusing their interest on alternative immunostimulatory agents. Here, we summarize recent findings on the use of TLR agonists in cancer patients and discuss how the clinical evaluation of FDA-approved and experimental TLR ligands has evolved since the publication of our first Trial Watch dealing with this topic.

Consensus guidelines for the detection of immunogenic cell death

“…Nonetheless, HMGB1-deficient malignant cells exposed to ICD inducers fail to elicit adaptive immune responses upon inoculation into immunocompetent syngeneic mice, a defect that can be corrected by the co-administration of synthetic TLR4 ligands. [225][226][227][228] Together with the notion that Tlr4 ¡/-mice fail to perceive anthracycline-treated syngeneic cells as immunogenic, 41,229 this observation demonstrates the importance of the HMGB1-TLR4 signaling axis for ICD.…”

LocalSalmonellaimmunostimulation recruits vaccine-specific CD8 T cells and increases regression of bladder tumor

“…Our data suggest that this vaccine should be added to the list of TLR agonists to be tested in oncologic indications. 41 Expression of chemokines and ESL among CD4 T cells (black symbols) or among CD8 T cells (white symbols) is shown. ND: not detectable.…”

Trial Watch—Oncolytic viruses and cancer therapy

“…Among this abundant literature, we found of especial interest the works of (1) Arulanandam and colleagues (Ottawa Hospital Research Institute, Ottawa, Canada), who discovered that a transcriptional modulator operating downstream of vascular endothelial growth factor receptors (VEGFRs) 208,209 suppresses Type I interferon (IFN) responses, 210 hence sensitizing the tumor vasculature to infection by oncolytic viruses, 211 and found that microtubule-destabilizing agents commonly employed in the clinic (e.g., paclitaxel) 212,213 synergize with oncolytic virotherapy by disrupting the translation of Type I IFN-coding mRNAs and by exacerbating the demise of cancer cells provoked by the cytopathic effect; 214 (2) Nishio and collaborators (Baylor College of Medicine, Houston, TX, US), who reported that an oncolytic adenovirus genetically engineered to express interleukin-15 (IL-15) and chemokine (C-C motif) ligand 5 (CCL5, also known as RANTES) improved the therapeutic potential of adoptively transferred T cells expressing a chimeric antigen receptor (CAR) 215,216 [218][219][220][221][222] a means to boost the replication (and hence the efficacy) of an oncolytic HSV-1 strain; 223 (4) Parrish and co-authors (St James's University Hospital, Leeds, UK), who discovered that an oncolytic reovirus enhances the capacity of the FDA-approved CD20-targeting monoclonal antibody rituximab 224,225 to stimulate antibody-dependent cellular cytotoxicity; 226 , who discovered that autonomous parvoviruses are endowed with a rather advantageous feature for the development of novel oncolytic virotherapies, namely, they neither trigger nor inhibit Type I IFN responses in normal and malignant cells; 236 (11) Zloza and coauthors (Rush University Medical Center, Chicago, IL, US), who suggested that the downregulation of leukocyte immunoglobulin-like receptor, subfamily B (with TM and ITIM domains), member 1 (LILRB1, also known as ILT2) in peripheral blood mononuclear cells may constitute a reliable biomarker of therapeutic responses to oncolytic virotherapy in cancer patients; 237 (12) Liikanen and colleagues (University of Helsinki, Helsinki, Finland), who propose that the circulating levels of the damage-associated molecular pattern high mobility group box 1 (HMGB1) [238][239][240][241] at baseline may constitute a robust prognostic factor as well as a predictive indicator of disease control up...…”