Abstract 2669: Antitumor activity of the CMP-001 (TLR9 agonist) alone or combined with immune modulators in syngeneic tumor models

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.2669-2669
• Main Authors: Bichat, Francis, Maubant, Sylvie, Mirjolet, Jean-François, Slos, Philippe, Krieg, Arthur M., Morris, Aaron
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-2669

Targeted blockade of checkpoint inhibitors such as CTLA-4 or PD-1 with antagonist monoclonal antibodies (mAbs) has shown impressive and durable clinical responses in patients with advanced cancer. An alternative strategy to boost anti-tumor immunity is to promote T cell activation through co-stimulatory receptors such as OX40 and 4-1BB. OX40 is of particular interest as treatment with an activating anti-OX40 mAb augments T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity. However, each of these agents benefits only a subset of patients, highlighting the critical need for more effective combinatorial therapeutic strategies. Toll-like receptor 9 (TLR9) agonist CpG oligodeoxynucleotides (ODN) are candidates to promote an anti-tumor immune response. CMP-001, a CpG-A ODN formulated within a virus-like particle, is designed to activate TLR9 (the receptor for CpG-A) in tumor-associated plasmacytoid dendritic cells (pDC) within the tumor or tumor-draining lymph nodes. Resting or immature pDC promote tumor growth, but when activated by CpG-A, the resulting mature pDC promote a robust anti-tumor immune response. Activation of pDC causes secretion of very large quantities of type I interferons, increased expression of costimulatory molecules, and recruitment and activation of other DC subsets to enhance tumor antigen presentation to T cells, culminating in the generation of effective anti-tumor T cell responses. The preclinical efficacy of intratumorally administered CMP-001 alone or in combination with an intraperitoneally administered PD-1 antagonist and/or an OX40 agonist was examined and assessed in a variety of syngeneic tumor models: CT-26 colon tumor model, MBT-2 bladder tumor model, RenCa kidney tumor model, 4T1 breast tumor model and LLC-1 lung tumor model. Tumors were implanted into left and right flanks while only one tumor was injected with CMP-001. In addition to body weight and overall survival, tumor volume was monitored on both flanks to assess direct and abscopal/systemic anti-tumor activity. Some discrepancies were observed between evaluated syngeneic tumor models with non-responders (LLC-1, 4T1) and responders (CT-26, MBT-2, RenCa). The most efficacious results were registered in the CT-26 model. Each therapeutic yielded weak activity as a single agent, which improved when combined with another treatment modality. The best therapeutic efficacy was obtained with the combination of all three agents resulting in cure