Supra-Additive Effect Of Imo-4200, A Novel Tlr7 And Tlr8 Dual Agonist, With Rituximab And Cytotoxics In Preclinical Models Of Hematologic Malignancies

e13076 Background: IMO-4200, a dual agonist of toll-like receptors (TLR) 7 and 8, induces potent Th-1 immune responses and exerts significant antitumor effects in a number of tumor models. In this study, we evaluated IMO-4200 in combination with rituximab and bendamustine or rituximab and fludarabine in human lymphoma xenograft models. Methods: Mice implanted IV with Ramos cells were treated with IMO-4200 50 mg/kg SC every other day x 5, rituximab 10 mg/kg IP every other day x 5, both agents or saline control starting at day 8. The addition of bendamustine 15 mg/kg IP daily x 3 was then tested. In a second experiment in human B-cell lymphoma Raji xenografts, we used fludarabine 250 mg/kg IP instead of bendamustine plus 4 additional IMO-4200 injections. In a third set of experiments conducted in vitro, we monitored the impact of IMO-4200 on rituximab-mediated antibody-dependent cytotoxicity (ADCC) and direct apoptosis of the tumor cells. Results: The table shows that IMO-4200 significantly increased survival when added to rituximab alone and when combined with both rituximab and either cytotoxic. In addition, IMO-4200 enhanced the ADCC of rituximab on Raji and Granta human lymphoma cell lines. It also sensitized human B-cell lymphoma Ramos cells to rituximab-induced apoptosis. Conclusions: IMO-4200 enhances the antitumor activity of rituximab and standard cytotoxic agents used in non-Hodgkin's lymphoma or other hematologic malignancies. IMO-4200 has been selected as the lead candidate for clinical development. Bendamustine Fludarabine Median survival (days) P value vs. control Median survival (days) P value vs. control Control 23 18 – IMO-4200 25 0.233 ND – Rituximab 36 <0.01 24 <0.01 IMO-4200 + rituximab 45 0.012* 29 <0.01* Cytotoxic agent + rituximab 49 <0.01* 32 <0.01* IMO-4200 + rituximab + cytotoxic agent 59 0.026† 37 0.012† * vs rituximab; † vs rituximab + cytotoxic agent; ND, not done.