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Poster display session

4841 - The TLR9 agonist lefitolimod modulates tumor microenvironment and improves anti-tumor effect of checkpoint inhibitors in vivo

Date

11 Sep 2017

Session

Poster display session

Presenters

Kerstin Kapp

Citation

Annals of Oncology (2017) 28 (suppl_5): v573-v594. 10.1093/annonc/mdx390

Authors

K. Kapp1, B. Volz1, D. Oswald1, B. Wittig2, M. Schmidt1

Author affiliations

  • 1 Translational Research, Mologen AG, 14195 - Berlin/DE
  • 2 Foundation Institute Molecular Biology And Bioinformatics, Freie Universitaet Berlin, 14195 - Berlin/DE
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Resources

Abstract 4841

Background

Preclinical and ongoing clinical studies support the use of TLR9 agonists for immunotherapeutic approaches. Lefitolimod (MGN1703) is a covalently-closed dumbbell-like immune surveillance reactivator with broad immunomodulatory effects on the innate and adaptive immune system. Lefitolimod is currently evaluated in a phase 3 trial in mCRC patients (IMPALA), a phase 2 trial in SCLC patients (IMPULSE) and in two phase 1/2 trials, (i) in solid tumors in combination with the checkpoint inhibitor ipilimumab and (ii) in HIV patients (TEACH).

Methods

In several murine tumor models lefitolimod reduced tumor growth. Since the mode-of-action of lefitolimod starts upstream of the initiation points of checkpoint inhibitors like anti-CTLA-4 or anti-PD-1/anti-PD-L1 combinatory approaches may result in an enhanced anti-tumor effect. Therefore, two syngeneic murine models – the colon carcinoma CT26 and the lymphoma A20 model – were used for evaluation of the anti-tumor effect of lefitolimod with checkpoint inhibitors. In the CT26 model the influence of lefitolimod on tumor microenvironment (TME) was analysed.

Results

Treatment with anti-PD-L1 (i.p.) had no effect on tumor growth in the CT26 model, whereas addition of lefitolimod (s.c.) to anti-PD-L1 led to a clear anti-tumor effect (tumor growth inhibition, TGI 48%). This combinatory effect was even more pronounced in the A20 model where treatment with anti-PD-1 (i.p.) alone had a moderate anti-tumor effect which was vastly increased by the combination (TGI – anti-PD-1: 46%, anti-PD-1/lefitolimod 99%). Moreover, in the CT26 model an anti-tumor response to lefitolimod (i.tu.) was associated with increased infiltration of CD3 T-cells –more specifically CD8 T-cells – into the tumor of a CT26 model.

Conclusions

We showed that the member of dSLIM family of TLR9 agonists, lefitolimod, can enhance the limited anti-tumor effects of checkpoint inhibitors in murine colon carcinoma and lymphoma tumor models in vivo. The anti-tumor effect of lefitolimod is associated with TME modulation with increased T-cell infiltration. These data clearly support the combination of lefitolimod with checkpoint inhibitors in clinical trials.

Clinical trial identification

Legal entity responsible for the study

Mologen AG

Funding

Mologen AG

Disclosure

K. Kapp, B. Volz, D. Oswald, M. Schmidt: Employee of Mologen AG. B. Wittig: Consults Mologen AG and also receives funding from Mologen AG.

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