Background: Immunotherapy offers the potential for durable responses in a growing list of cancer indications. NKTR-214 is comprised of the cytokine IL2 conjugated o multiple PEG units. Upon in vivo administration some of these PEG molecules are released to leave activated IL2-conjugates that bind selectively at the IL2 receptor beta subunit (IL2Rβ). The active IL-2-conjugates favor proliferation of tumor-killing CD8+ memory T cells (CD8T) over immunosuppressive regulatory T cells (Treg) in the tumor microenvironment (Charych, JCO 2013, 31:15, Suppl. 1).We have also shown that NKTR-214 results in sustained exposure of drug in the tumor and robust immune system activation that translates between rodents and monkeys at safe doses, (AACR; Mol Cancer Ther 2013;12 (11 Suppl): Abstract B296). The receptor selectivity and improved pharmacokinetic profile leads to substantially improved single-agent efficacy and safety over the original IL-2 cytokine. Combinations of different checkpoint blockade antibodies have shown great promise clinically and in preclinical tumor models, highlighting the importance of targeting multiple immune activation pathways. Here we examine the combination of NKTR-214 with anti-CTLA4 antibody in murine breast and colon tumor models to explore the interaction of two mechanisms of action: checkpoint inhibition and direct CD8T cell activation via the IL-2 receptor beta.

Methods: Female BALB/c mice bearing established tumors implanted with CT-26 (Murine Colon Carcinoma) or EMT6 (Murine Mammary Carcinoma) cells were treated with single agent NKTR-214, murine anti-CTLA-4 antibody or the two agents in combination. NKTR-214 was administered at 0.8 mg/kg i.v. and anti-CTLA-4 at 100 μg/mouse i.p.

Results: In both the EMT6 breast and the CT-26 colon models, the combination of NKTR-214 with anti-CTLA-4 yielded significantly better tumor growth inhibition compared to either agent dosed alone. In the EMT6 model 10/12 animals were tumor free by day 20 in the combination arm and stayed tumor free until the end of study (60 days). Similarly in the CT-26 model, 8/12 animals were tumor free by day 25 in the combination arm and stayed tumor free until the end of study (day 60). Single agent anti CTLA-4 or NKTR-214 did not show significant tumor inhibition in either model. No toxicities were observed when NKTR-214 was combined with anti CTLA-4 antibody.

Conclusions: NKTR-214 is a highly differentiated immunotherapy with a new mechanism of action that shows efficacy both as a single agent (as previously shown in a mouse melanoma model) and in combination. Combining NKTR-214 mediated T cell activation with CTLA-4 blockade is highly synergistic in murine models of cancer and holds the promise for durable responses in patients.

Citation Format: Steve Lee, Murali Addepalli, Ute Hoch, Rhoneil Pena, Payal Shirsat, Yolanda Kirksey, Stephen K. Doberstein, Deborah Charych, Seema Kantak. Synergy between an engineered cytokine, NKTR-214, and CTLA-4 blockade in murine colon and breast tumor models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5032. doi:10.1158/1538-7445.AM2014-5032