Abstract 2644: SY-1425, a selective RARα agonist, induces high levels of CD38 expression in RARA-high AML tumors creating a susceptibility to anti-CD38 therapeutic antibody treatment
Authors: Austgen Kathryn , McKeown Michael R. , Smith Darren , Lee Emily , Fiore Chris , Eaton Matthew L. , Fritz Christian , Lodie Tracey , Olson Eric 
Published: July 2017

CD38 is a cell surface protein expressed primarily on white blood cells and considered a marker of differentiation initiation. CD38 is involved in the immune system by engaging cross-talk with T and B cells as well as activation of NK cells. In multiple myeloma (MM), a subset of tumor cells have high CD38 expression (CD38hi), which has led to the development of effective anti-CD38 therapeutic antibodies, such as daratumumab (DARA). Thus, cancer cells that express CD38 can be selectively targeted for elimination by the immune system using these therapeutic antibodies. In multiple myeloma, DARA is most effective in patients whose tumor cells are CD38hi. In contrast, CD38 expression in AML tumors is generally observed to be negative (CD38neg) or dim (CD38dim), and DARA has not shown activity in preclinical AML models. We previously reported that SY-1425, a clinical stage RARα agonist with improved pharmacokinetics, potency, and selectivity over pan-retinoic acid agonists, induces differentiation in non-APL AML cell lines and primary patient samples with a RARA super-enhancer associated biomarker (RARA-high). Since CD38 was found to be among the most differentially expressed genes in response to SY-1425, we hypothesized that SY-1425 mediated CD38 induction to levels comparable to MM may sensitize RARA-high AML cells to anti-CD38 therapy. We demonstrate that SY-1425 treatment of four RARA-high AML cell lines and four RARA-high primary AML patient PBMCs induces the CD38hi phenotype, as measured by flow cytometry, similar to that found in the DARA sensitive MM cells. In contrast, we see no induction in RARA-low cell lines. We then demonstrated the activity of the SY-1425 and DARA combination in an ex vivo NK cell co-culture assay. Two RARA-high AML cell lines treated with SY-1425 and DARA were co-cultured with NK cells and monitored for both antibody dependent cell-mediated cytotoxicity (ADCC) and NK cell activation by interferon gamma production. The combination of SY-1425 and DARA led to a six-fold increase in tumor cell death relative to the single agent controls, and 5-10 fold increases in NK cell activation is observed only in the SY-1425 and DARA combination treatment of RARA-high AML cell lines. Neither single agent, when administered alone, resulted in ADCC. Furthermore, a RARA-low AML cell line does not respond in the ADCC assay following the combination treatment due to the lack of CD38 induction in this SY-1425 insensitive line. In summary, we have identified a novel and rational combination treatment approach for a subset of patients with RARA-high AML. By inducing the expression of CD38, SY-1425 in combination with DARA elicits tumor cell death and NK cell activation. Based on these findings, a phase 2 clinical study with SY-1425 in combination with an anti-CD38 antibody is planned in AML using an RARA biomarker patient selection strategy.

Citation Format: Kathryn Austgen, Michael R. McKeown, Darren Smith, Emily Lee, Chris Fiore, Matthew L. Eaton, Christian Fritz, Tracey Lodie, Eric Olson. SY-1425, a selective RARα agonist, induces high levels of CD38 expression in RARA-high AML tumors creating a susceptibility to anti-CD38 therapeutic antibody treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2644. doi:10.1158/1538-7445.AM2017-2644