TLR9 agonist lefitolimod to improve antitumor effect of checkpoint inhibitors in vivo.

Abstract

e14625 Background: TLR9 agonists are potent activators of the immune system via induction of cellular and humoral responses. 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 (ISR) with a broad immunomodulatory potential. Due to promising data from a phase 2 trial (IMPACT) as maintenance therapy after first-line chemotherapy in mCRC patients lefitolimod is recently evaluated in a phase 3 trial in mCRC patients (IMPALA). Furthermore, lefitolimod is currently investigated in a phase 2 trial in SCLC patients (IMPULSE) and in a phase 1 / 2 trial in HIV patients (TEACH). Methods: It was shown that lefitolimod reduces tumor growth in several murine tumor models. 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 a combinatory approach may result in an enhanced anti-tumor effect. Therefore, two syngeneic murine models were used – a colon carcinoma CT26 and a lymphoma A20 model – for evaluation of the anti-tumor effect in vivo. Results: In the CT26 model treatment with anti-PD-L1 (i.p.) had no effect on the tumor growth, whereas addition of lefitolimod (s.c.) to anti-PD-L1 led to an anti-tumor effect (tumor growth inhibition, TGI 48%) which consequently resulted in prolonged survival of the mice. 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%). Conclusions: In conclusion, we showed that lefitolimod, a member of dSLIM® family of TLR9 agonists and an ISR, can enhance the limited anti-tumor effects of checkpoint inhibitors in pilot studies in murine colon carcinoma and lymphoma tumor models in vivo. These data show the promising potential for the combination with checkpoint inhibitors. Notably, a clinical trial in cooperation with MD Anderson evaluating the benefit of lefitolimod in combination with ipilimumab is currently ongoing.