MDSC & Cancer
Emerging data have demonstrated that tumor associated immune suppressor cells, such as MDSC, actively suppress T cell responses and promote immune suppression in solid tumors (1). Multiple studies in a broad spectrum of malignancies have shown that the accumulation of MDSC within tumors is associated with a poor clinical outcome (2). In addition, these studies have shown that resistance to anti-cancer therapies, including immune checkpoint blockade, may be driven by increased MDSC (3). MDSC are myeloid cells and can be identified in humans based on cell surface antigen expression (4). CD33 has been shown to be highly expressed on tumor-associated immune suppressor cells, including MDSC, making this antigen an attractive target for antibody-based therapeutics (5, 6). Binding of S100A9 to CD33 induces secretion of IL10 and tumor growth factor (TGF)-β by immature myeloid cells, and MDSC expansion (7). Tumor expressed sialoglycans, which could act as ligands for CD33, may be involved in the recruitment of these potent immune suppressive cells into the tumor microenvironment.
AMV564 selectively reduces MDSC in patients with AML based on results from the on-going first-in-human clinical trial (AMV564-101). In ex vivo assays, AMV564 has been shown to eliminate MDSC, as defined by high CD33 expression, in a dose-dependent manner, in bone marrow samples from patients with MDS and peripheral blood samples from patients with melanoma (8, 9). In parallel AMV564 restored immune homeostasis, promoting T cell proliferation and production of interferon (IFN)-γ by both CD8 and CD4 T cells. CD8 and CD4 T cell responses were further enhanced by AMV564 in the context of checkpoint blockade using anti-PD1.
The published data combined with the clinical experience with AMV564 suggest that targeting solid tumors with AMV564 may result in tumor responses in patients resistant to standard of care therapies including immune checkpoint inhibitors.
(1) Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res. 2017 Jan;5(1):3-8.
(2) Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci. 2014; 1319:47–65.
(3) Meyer C, Cagnon L, Costa-Nunes CM, et al. Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab. Cancer Immunol Immunother. 2014; 63(3): 247–257.
(4) Elliott LA, Doherty GA, Sheahan K, Ryan EJ. Human tumor- infiltrating myeloid cells: phenotypic and functional diversity. Front Immunol. 2017 Feb 6; 8:86.
(5) Ortiz ML, Kumar V, Martner A, et al. Immature myeloid cells directly contribute to skin tumor development by recruiting IL-17–producing CD4+ T cells. J Exp Med. 2015; 212(3):351–367.
(6) Data on file.
(7) Chen X, Eksioglu EA, Zhou J, et al. Induction of myelodysplasia by myeloid-derived suppressor cells. J Clin Invest. 2013 Nov;123(11):4595-611.
(8) Cheng P, Eksioglu E, Chen X, et al. Immunodepletion of MDSC by AMV564, a novel tetravalent bispecific CD33/CD3 T Cell engager restores immune homeostasis in MDS in vitro. Blood. 2017; 130:51 (abstract).
(9) Data on file.