Trial watch: Toll-like receptor ligands in cancer therapy

ABSTRACT

Accumulating evidence indicates that Toll-like receptor (TLR) agonists proficiently (re)instore cancer immunosurveillance as immunological adjuvants. So far, three TLR agonists have been approved by regulatory agencies for use in oncological applications. Additionally, these immunotherapeutics have been extensively investigated over the past few years. Multiple clinical trials are currently evaluating the combination of TLR agonists with chemotherapy, radiotherapy, or different immunotherapies. Moreover, antibodies targeting tumor-enriched surface proteins that have been conjugated to TLR agonists are being developed to stimulate anticancer immune responses specifically within the tumor microenvironment. Solid preclinical and translational results support the favorable immune-activating effects of TLR agonists. Here, we summarize recent preclinical and clinical advances in the development of TLR agonists for anticancer immunotherapy.

KEYWORDS:

• Immunotherapy
• ampligen
• vidutolimod
• immune checkpoint blockers
• antibody

Abbreviations

CpG, cytosine-phosphate-guanosine dinucleotide; DC, dendritic cell; HER2, human epidermal growth factor receptor-2; IFN, interferon; i.p., intraperitoneally; i.t., intratumorally; i.v., intravenously; mAb, monoclonal antibody; MDSCs, myeloid-derived suppressor cells; MSS, microsatellite stable; NK, natural killer; ODN, oligodinucleotides; PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1; p.o., per os; s.c., subcutaneously; SCC, squamous cell carcinoma; RNA, ribonucleic acid; TLR, Toll-like receptor; TRAEs, treatment-related adverse events; Q3W, administered every 3 weeks.

Acknowledgments

GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; European Research Council Advanced Investigator Grand “ICD-Cancer,” Fondation pour la Recherche Médicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases (EJPRD); European Research Council (ICD-Cancer), European Union Horizon 2020 Projects Oncobiome and Crimson; Fondation Carrefour; Institut National du Cancer (INCa); Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); a Cancer Research ASPIRE Award from the Mark Foundation; the RHU Immunolife; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001.

Disclosure statement

JLN has no potential conflicts of interest to disclose. GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys, and Vascage. GK has been consulting for Reithera. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of EverImmune, Osasuna Therapeutics, Samsara Therapeutics, and Therafast Bio. GK is in the scientific advisory boards of Hevolution, Institut Servier and Longevity Vision Funds. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis, and metabolic disorders. GK’s wife, Laurence Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9 m, Tusk and Roche, was on the Board of Directors of Transgene, is a cofounder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. GK’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. The funders had no role in the design of the study, in the writing of the manuscript, or in the decision to publish the results.

Additional information

Funding

The author(s) reported that there is no funding associated with the work featured in this article.