Abstract 1727: Antitumor activity associated with dual targeting of CD38 and programmed death-1 (PD-1) pathways in preclinical models

Abstract

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.

Mechanisms of Resistance to Anti-CD38 Daratumumab in Multiple Myeloma

“…Chen et al [50] demonstrated that overexpression of CD38 is a mechanism of tumor escape from PD1/PDL1 axis blockade in that it suppressed CD8 + T cell function via ADO signaling. Consistent with these results, Bezman et al [51] showed an enhanced antitumor activity in MC38 and J558 mice treated with a combined therapy, suggesting that a dual targeting of CD38 and PD1 may represent a promising anti-MM therapeutic strategy. The synergic effect induced by anti-CD38 mAbs was related to a reduction in the frequency of immunosuppressive Tregs and MDSCs populations.…”

Immunotherapy in Multiple Myeloma

“…Indeed, pre-clinical data suggest that immunomodulatory activity of CD38 antibodies can be enhanced by combining a CD38 antibody with a PD-1/PD-L1 inhibitor. For example, in mouse models targeting the CD38 and PD-1 pathway in MM, lung cancer, and colon adenocarcinoma, the combination of a CD38 antibody and PD-1 antibody resulted in enhanced anti-tumor activity, when compared to targeting either pathway alone [60]. This was accompanied by increased T-cell infiltration and T-cell activation in the tumors with combined anti-CD38 and anti-PD-1 treatment [60].…”

“…For example, in mouse models targeting the CD38 and PD-1 pathway in MM, lung cancer, and colon adenocarcinoma, the combination of a CD38 antibody and PD-1 antibody resulted in enhanced anti-tumor activity, when compared to targeting either pathway alone [60]. This was accompanied by increased T-cell infiltration and T-cell activation in the tumors with combined anti-CD38 and anti-PD-1 treatment [60]. In addition, another group showed that CD38 expression is increased following therapy with a PD-L1 inhibitor in a lung cancer mouse model, which was associated with impaired CD8+ T-cell function, and the combination of a CD38 antibody with PD-L1 inhibitor showed enhanced anti-tumor activity [61].…”

“…How best to combine checkpoint inhibitors with existing myeloma therapies is another aspect which requires careful consideration. Pre-clinical data supporting the use of checkpoint inhibitors with monoclonal antibodies and even radiotherapy may provide avenues to design novel therapeutic regimens [60,140].…”

Anticorps anti-CD38 dans le myélome multiple

“…L'induction de l'expression du points de contrôle immunitaire PD-1 (programmed cell death-1) et de son ligand, PD-L1 (programmed cell deathligand 1), peut également contribuer au développement de résistances aux fonctions immunomodulatrices des anticorps anti-CD38 [39,40]. Des données précliniques montrent que l'association d'anticorps anti-PD-1/PD-L1 à des anticorps anti-CD38 pourraient présenter un intérêt thérapeutique afin d'améliorer la prise en charge des patients [41,42].…”