Antitumor activity of a synthetic agonist of TLR9 in preclinical lung cancer models

Abstract

2568 Background: Synthetic agonists of TLR9 induce potent Th1-type innate and adaptive immune responses. In the present study, we have studied antitumor activity of a synthetic agonist of TLR9 referred to as immune modulatory oligonucleotide (IMO) in lung cancer models either alone or in combination with chemotherapeutic agents. Methods: Two different models are evaluated. In one model, mice implanted peritoneally with 3LL-C75 lung carcinoma cells were administered with IMO or PBS once in every two days for six times for evaluating antitumor activity of IMO alone. In a second model, to evaluate combination treatment of IMO with Gemcitabine or cyclophosphamide, mice bearing subcutaneously implanted 3LL tumor were administered with peritumoral injections of IMO and i.p. injections of Gemcitabine or cyclophosphamide. Results and Conclusions: Administration of IMO to mice bearing 3LL-C75 lung carcinoma inhibited tumor growth. Tumor free mice from this study failed to grow tumor when rechallenged with 3LL-C75 lung carcinoma cells, suggesting tumor bearing mice administered with IMO developed memory responses for the same tumor. Further more, naïve mice adoptively transferred with splenocytes obtained from mice that remained tumor free from the above treatment group failed to grow tumor to a rechallenge with 3LL-C75 tumor cells. The co-administration of IMO with chemotherapeutic agents, Gemcitabine and cyclophosphamide resulted in enhanced antitumor effects in 3LL lung cancer model. The present studies show potent antitumor activity of IMO when administered alone and in combination with Gemcitabine and cyclophosphamide in preclinical lung cancer models. [Table: see text]