IMO-4200, a Novel TLR7 and TLR8 Dual Agonist, Enhances Antitumor Effect of Ofatumumab, Rituximab and Cytotoxics in Preclinical Models of Hematological Malignancies,

Abstract 3724

Background Toll-like receptors (TLR) are ideal targets for combination therapy of hematological malignancies as they modulate immune responses and can influence the tumor microenvironment through cytokine and chemokine induction. TLR-targeted agents have potential to treat hematological tumors by regulating the innate and acquired immune responses to cancer cells. We have previously shown that IMO-4200, a TLR7 and TLR8 dual agonist enhanced the antibody-dependent cell cytotoxicity (ADCC) of rituximab on Raji and Granta human lymphoma cell lines in vitro. Furthermore, we demonstrated that combining the agonist with rituximab resulted in long-term tumor-free survival of mice implanted i.v. with Raji B cell lymphoma or HBL-2 mantle cell lymphoma xenografts.

Materials and methods In a first study, we evaluated the antitumor effect of IMO-4200 and ofatumumab, a fully human anti-CD20 antibody, in mice challenged with Raji tumor xenografts. SCID mice implanted i.v. with Raji cells were treated with 50mg/kg agonist (s.c., twice weekly for 5 weeks), 10mg/kg ofatumumab (i.p. 5 times in 3 weeks) or PBS. Treatment was initiated at day 8. In a second experiment we evaluated IMO-4200 in combination with rituximab and bendamustine or rituximab and fludarabine in human lymphoma xenograft models. Mice implanted i.v. with Ramos cells were treated with 50 mg/kg of IMO-4200 (s.c., every other day for 5 times), 10 mg/kg rituximab (i.p., every other day for 5 times), the combination of the two agents or PBS starting at day 8. Lastly, we repeated the fludarabine study design using bendamustine, 15 mg/kg, i.p., daily for 3 days, as the cytotoxic agent.

Results – ofatumumab combination – The control group that received PBS developed disseminated systemic disease with a median survival of 21 days and all died within 26 days. Treatment with ofatumumab alone led to moderate tumor growth inhibition with a median survival of 31 days (p=0.0036); however, all of these mice developed lymphoma and died within 34 days. Treatment of mice with the combination of agonist and ofatumumab resulted in increased survival of 45% of mice (p=0.003 compared to antibody alone) with a median survival of 56 days.

Results – rituximab/chemotherapy combinations – Mice that received PBS developed systemic disease with a median survival of 23 days. The median survival of mice treated with IMO-4200 did not differ significantly (25 days, p = 0.233), whereas rituximab increased median survival to 36 days (p < 0.01). In contrast, the combination of IMO-4200 and rituximab extended median survival to 45 days (p = 0.0121 compared to rituximab alone). Similarly, rituximab and bendamustine increased median survival to 49 days. The triple combination of IMO-4200, rituximab and bendamustine augmented median survival to 59 days (p = 0.023 compared to rituximab plus IMO-4200; p =0.026 compared to rituximab plus bendamustine). Similar enhancement of antitumor activity was observed in human B-cell lymphoma Raji xenografts when IMO-4200 was combined with rituximab and fludarabine.

Conclusions Our data suggest that IMO-4200, a novel dual agonist of TLR7 and TLR8 has the potential to increase the efficacy of rituximab as well as other novel and standard agents in the treatment of non-Hodgkins lymphoma and other hematological malignancies.