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1169 Systemic administration of TLR7/8 agonist micelles triggers a potent anti-tumor response mediated by neutrophils as primary effector cells followed by establishment of an immune memory response
  1. Simon Jensen1,
  2. Esben Christensen2,
  3. Morten Just Petersen1,
  4. Anders Hansen2,
  5. Martin Bak2,
  6. Camilla Stavnsbjerg2,
  7. Svetlana Panina1 and
  8. Thomas Andersen2
  1. 1MonTa Biosciences, Lyngby, Denmark
  2. 2Danish Technical University, Lyngby, Denmark


Background Clinical use of TLR7/8 agonists is currently restricted to topical application of Imiquimod for treatment of superficial basal cell carcinoma since systemic administration is a challenge due to dose-limiting toxicity. Here, we present data to overcome this challenge using a novel micelle-based drug delivery technology containing a lipid-anchored TLR7/8 agonist for intravenous administration. The MBS8 formulation shows good efficacy in mouse cancer models, is well tolerated in rodents and non-human primates and is currently being tested in clinical studies (NCT04855435).

Methods MBS8 was tested in 12 syngeneic mouse cancer models as monotherapy or in combination anti-PD-1 and anti-PD-L1 antibodies. MBS8 was administered IV as slow bolus on up to 5 occasions with different time schedules. Tumors and spleens were analysed using histology, immunohistochemistry, ELISPOT and flow cytometry. Phenotyping of tumor immune microenvironment was done using flow cytometry and Nanostring analyses. Safety and tolerability were tested in mice, rats and cynomolgus monkeys.

Results In several syngeneic mouse tumor models, MBS8 led to complete eradication of established tumors. The complete responders showed tumor rejection upon re-challenge. In these mice, a CD8+-dependent tumor-specific immune memory response was evident. Tumors demonstrated a massive tissue necrosis (>80%) within 24-48h after the first drug administration and showed massive neutrophil infiltration 6h after dosing. Antigen specific CD8+ T-cells were detected in tumors 24 hours after treatment with increased CD8+:Treg cell ratio and enhanced antigen presentation in tdLN.

MBS8 showed both additive and synergistic effect when combined with anti-PD-1 or anti-PD-L1 antibody treatment. Moreover, in tumors being resistant to anti-PD-1 treatment, co-administration of MBS8 reverted sensitivity to anti-PD-1 treatment in a synergistic manner.

Conclusions MBS8 showed significant anti-cancer activity in multiple in vivo solid tumor models when administered either as monotherapy or in combination with ICIs.

MBS8 demonstrated a novel mode of action with neutrophils playing a central role as primary effector cells causing a rapid killing of tumor cells. Further, an adaptive immune response was initiated including generation of tumor antigen-specific CD8+ cells and establishment of immune memory response.

MBS8 was well tolerated in rodents and cynomolgus monkeys at dose levels above therapeutic effective doses identified in mice, thus providing a good therapeutic window.

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