https://orcid.org/0000-0002-6081-9558
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ABSTRACT
Toll-like receptor 3 (TLR3) agonists such as polyinosinic:polycytidylic acid (poly(I:C)) have immunostimulatory effects that can be taken advantage of to induce anticancer immune responses in preclinical models. In addition, poly(I:C) has been introduced into clinical trials to demonstrate its efficacy as an adjuvant and to enhance the immunogenicity of locally injected tumors, thus reverting resistance to PD-L1 blockade in melanoma patients. Here, we report the pharmacokinetic, pharmacodynamic, mechanistic and toxicological profile of a novel TLR3 agonist, TL-532, a chemically synthesized double-stranded RNA that is composed by blocks of poly(I:C) and poly(A:U) (polyadenylic – polyuridylic acid). In preclinical models, we show that TL-532 is bioavailable after parenteral injection, has an acceptable toxicological profile, and stimulates the production of multiple chemokines and interleukins that constitute pharmacodynamic markers of its immunostimulatory action. When given at a high dose, TL-532 monotherapy reduced the growth of bladder cancers growing on mice. In addition, in immunodeficient mice lacking formylpeptide receptor-1 (FPR1), TL-532 was able to restore the response of orthotopic subcutaneous fibrosarcoma to immunogenic chemotherapy. Altogether, these findings may encourage further development of TL-532 as an immunotherapeutic anticancer agent.
Disclosure statement
O.K is a scientific co-founder of Samsara Therapeutics. G.K. received research support by Tollys. S.T., M. B-J., M.B., C.P. C.R., B.M. and B.W. were full-time employees of Tollys. Outside of this work, GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, and Vascage. 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’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.
Abbreviations
| CTX | = | Cyclophosphamide |
| DC | = | dendritic cell |
| iniDC | = | inducible immortalized dendritic cell |
| i.p. | = | intraperitoneally |
| i.t. | = | intratumorally |
| i.v. | = | intravenously |
| MHC-I | = | major histocompatibility complex class I |
| MTX | = | mitoxantrone |
| OVA | = | ovalbumin |
| pAU | = | polyadenylic:polyuridylic acid |
| pIC | = | polyinosinic:polycytidylic acid |
| ROI | = | region of interest |
| s.c. | = | subcutaneously |
| WT | = | wildtype |
Author contributions
J.L.N, S.T., S.A.S, M. B-J., P.L, M.B., Y.P., C.P., L.Z., M.M., C.R., M. P-L, and B.M. performed experiments; O.K., G.K. and B.W. conceived the study and wrote the paper.
Data availability statement
All data are available from the corresponding authors upon reasonable request.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2227510