Background: Blockade of the programmed death-1 (PD-1) pathway has shown efficacy across a range of tumor types. However, some tumors do not respond and a combination strategy with other treatments may be required. CD38, a leukocyte receptor and ectoenzyme, was recently shown to be upregulated following PD-1 pathway blockade in mouse tumor models (Chen et al. ASCO-SITC 2017). Daratumumab is a fully human monoclonal antibody (mAb) that binds to CD38. It has been shown to exhibit immunomodulatory properties in patients with multiple myeloma (Krejcik et al. Blood. 2016). Studies in syngeneic mouse models and in vitro assays were conducted to investigate the potential of targeting CD38 in combination with anti-PD-1 to increase antitumor response.

Methods: mAbs targeting mouse CD38 (mCD38-mg2a; mCD38) and mouse PD-1 (mPD1-mIgG1-D265A; mPD-1) were tested alone or in combination in several syngeneic models: colon adenocarcinoma (MC38), plasmacytoma (J558), and lung carcinoma (M109). The effect of these mAbs on the phenotype and functionality of tumor-infiltrating and circulating lymphocytes was evaluated using flow cytometry and immunohistochemistry. In addition, the effect of daratumumab on human regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) was assessed.

Results: Combined anti-mCD38/anti-mPD-1 mAb treatment enhanced tumor regression and extended survival compared with single-mAb treatment in mouse tumor models. In the MC38 model (n=10/group), 55% of mice were tumor free (TF) following combined treatment, whereas 0% and 25% were TF following individual administration of anti-mCD38 or anti-mPD-1 mAbs, respectively. Similar effects were observed in J558- and M109-bearing mice (n=10/group for both models): with combined treatment, 85% of J558 and 20% of M109 mice were TF, compared with 50% (J558) and 0% (M109) for anti-mCD38 and 25% (J558) and 0% (M109) for anti-mPD-1 mAbs, respectively. Enhanced antitumor activity with combination treatment was associated with increased infiltration and activation of intratumoral CD4⁺ and CD8⁺ T cells, as well as increased levels of Ki67 on circulating T cells in MC38 and J558 models. The antitumor activity of anti-mCD38 mAb was dependent on active Fc function, suggesting that CD38⁺ cells may limit antitumor response. Consistent with this hypothesis, anti-mCD38 mAb led to a reduction in the frequency of CD38⁺ immunosuppressive Tregs and MDSC populations in mice. In vitro, daratumumab mediated antibody-dependent cellular cytotoxicity of human Tregs and led to the depletion of human monocytic MDSCs in blood of patients with lung cancer (n=17).

Conclusion: These results demonstrate the combined effect of targeting both CD38 and PD-1 pathways in regulating antitumor immunity, and suggest that dual targeting of CD38 with daratumumab and PD-1 with nivolumab may represent a promising combination strategy for treating cancer.

Citation Format: Natalie A. Bezman, Michelle Kinder, Amy D. Jhatakia, Bethany K. Mattson, Darlene Pizutti, Edward W. Thompson, Dorie A. Capaldi, Mark W. Mendonca, Aravind Anandam, Gopal Dhar, Lavanya Kovvuri, Archana Devi, Swagatam Ray, Vivek Surse, Elizabeth Saravia, Robert F. Graziano, Natalie A. Hutnick, Alan Korman. Antitumor activity associated with dual targeting of CD38 and programmed death-1 (PD-1) pathways in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1727.