On March 7, 2022 Tollys, a biopharmaceutical company developing TL-532, the first anti-cancer immunotherapy based on a synthetic toll-like receptor 3 (TLR3) specific agonist, reported that it has entered into a sponsored research agreement with Gustave Roussy, the leading cancer center in Europe (Press release, Tollys, MAR 7, 2022, View Source [SID1234609589]).
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Professor Guido Kroemer’s team will evaluate the effects of TL-532 in the context of FPR1 deficiency using methods similar to those recently published in the original research article entitled ‘A TLR3 Ligand reestablishes chemotherapeutic responses in the context of FPR1 deficiency’. These studies were conducted with polyinosinic:polycytidylic acid (pIC), a research grade TLR3 agonist. In comparison with agonists of TLR 2, 4, 5, 6, 7, 8 and 9, only the TLR3 agonist pIC was able to restore deficient chemotherapeutic responses in mice lacking FPR1, suggesting a personalized strategy for compensating for the FPR1 defect with a TLR3 agonist.
TL-532 is developed by Tollys and is a specific TLR3 agonist with a defined 70 base pair sequence of double-stranded RNA (dsRNA), produced by chemical synthesis, which can meet today’s quality manufacturing standards for new molecular entities.
"We are very eager to show that TL-532 can restore deficient chemotherapeutic responses in the model of Prof Kroemer’s team, because FPR1 deficiency is a common genetic disorder and there is a good chance that, in the future, patients with FPR1 deficiency may derive critical benefits from a treatment with TL-532," said Vincent Charlon, CEO of Tollys.
About FPR1 Deficiency
For anthracycline-based chemotherapy to be immunogenic, dying cancer cells must release annexin A1 (ANXA1) that subsequently interacts with the pattern recognition receptor, formyl peptide receptor 1 (FPR1), on the surface of dendritic cells (DC). Approximately 30% of individuals bear loss-of-function alleles of FPR1, calling for strategies to ameliorate their anticancer immune response. Le Naour et al. (Cancer Discovery 2021;11:408-23), showed that immunotherapy with a ligand of Toll-like receptor-3, polyinosinic:polycytidylic acid (pIC), restores the deficient response to chemotherapy in tumors lacking ANXA1 developing in immunocompetent mice or those of normal cancers growing in FPR1-deficient mice. This effect was accompanied by improved DC-and T-lymphocyte–mediated anticancer immunity. Of note, carcinogen-induced breast cancers precociously developed in FPR1-deficient mice as compared with wild-type controls. A similar tendency for earlier cancer development was found in patients carrying the loss-of-function allele of FPR1. These findings have potential implications for the clinical management of FPR1-deficient patients.
About TL-532
TL-532 is the first synthetic specific TLR3 agonist with a proprietary defined doublestranded RNA sequence. As such, TL-532 has the potential to be the best-in-class and firstto-market TLR3 agonist. TL-532 was shown to have a triple mechanism of action inducing 1) death by apoptosis selective to cancer cells-not in normal cells-, leading to the in-situ release of tumor specific antigens, 2) activation of the myeloid dendritic cells of the immune system to mount a specific T-cell response against the tumor antigens and 3) a switch of the tumor microenvironment by producing cytokines and chemokines which are unfavorable to tumor development. The result is the immunogenic cell death of tumor cells, accompanied by an auto-vaccination preventing the recurrence of cancer.