LAUSR

Purpose: Mechanistic findings in preclinical studies demonstrate that antibody blockade of Semaphorin 4D (SEMA4D, CD100) reduces expansion of MDSC and shifts the balance of immune cells within the TME to facilitate tumor rejection. Efficacy is further enhanced when combined with various immunotherapies. Design of phase 1/2 combination trials of VX15/2503, a humanized IgG4 antibody targeting SEMA4D, with immune checkpoint inhibition will be presented. Methods: Anti-SEMA4D antibodies were evaluated alone and in combination with other immunotherapies in various preclinical models. Antitumor activity and immune response was characterized by immunohistochemistry, flow cytometry, functional assays, and cytokine, chemokine, and gene expression analysis. A phase I trial for single agent VX15/2503 was completed. Results: SEMA4D restricts migration of monocytes and promotes expansion of suppressive myeloid cells in vitro. Strong expression of SEMA4D at the invasive margins of actively growing tumors in vivo restricts the infiltration and modulates polarization of leukocytes in the TME. Antibody blockade of SEMA4D facilitated recruitment of activated DCs and T lymphocytes in preclinical models. MDSCs were significantly reduced in tumor and blood following treatment, and new data characterizing MDSC function in preclinical models will be described. A significant shift towards increased Th1 cytokines (IFNg, TNFa) and CTL-recruiting chemokine CXCL9, with concurrent reduction in Treg-, MDSC- and M2-macrophage promoting chemokines (CCL2, CXCL1, CXCL5,) was also observed. Accordingly, Teff:Treg ratio (3x, p Citation Format: Elizabeth E. Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, John E. Leonard, Terrence L. Fisher, Clint Allen, Paul Clavijo, Siwen Hu-Lieskovan, Antoni Ribas, Ernest S. Smith, Maurice Zauderer. Targeting the tumor microenvironment with first-in-class Semaphorin4D MAb for combination immunotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B199.