Abstract 1545: Altered myeloid and lymphoid composition of tumor microenvironment following anti-SEMA4D and immune checkpoint combination therapies
Authors: Elizabeth E. Evans, Terrence L. Fisher, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Desa Rae Pastore, Maria Scrivens, Alan Howell, Leslie Balch, John E. Leonard, Clint Allen, Paul E. Clavijo, Gregory Lesinski, Christina Wu, Conor Steuer, Nabil F. Saba, Brian Olson, Siwen Hu-Lieskovan, Antoni Ribas, Emily G. Greengard, Ernest S. Smith, Maurice Zauderer
Journal: Cancer Research (2019)

Abstract Anti-semaphorin 4D (SEMA4D, CD100) blocking antibody promotes immune infiltration, reduces immunosuppressive myeloid cells, and enhances T cell activity and tumor growth inhibition in combination with various immunotherapies in preclinical animal models. Clinical trials of immune checkpoint inhibitors (ICI) in combination with pepinemab (VX15/2503), humanized anti-SEMA4D antibody, are currently underway in several cancer indications. SEMA4D exerts multi-faceted effects within the tumor microenvironment by creating a barrier at the tumor-stroma margin to restrict immune cell infiltration and promote immunosuppressive activity of myeloid-derived cells. Blocking antibody to SEMA4D directly enhanced M1/M2 ratio and reduced both expression of chemokines that recruit MDSC and the ability of MDSC to suppress T cell activity. Antibody blockade simultaneously restored the ability of dendritic cells and cytotoxic T cells to infiltrate the TME, increasing ratio of Teffector to Tregulatory cells, in syngeneic tumor models. Importantly, anti-SEMA4D MAb enhanced the activity of co-administered immunotherapies, including antibodies to PD1, CTLA-4, and LAG3, epigenetic modulators, and additional novel immunomodulatory combinations in murine breast, colon, head and neck, and melanoma tumor models. New data will describe development and application of methods to assess immune phenotype and biomarkers in translational and clinical studies. These include flow cytometry and whole slide scans of multiplex IHC panels to examine MDSC, M1/M2 macrophage, monocytes, activated DC, B cells, exhausted, activated and stem-like populations of T cells in clinical samples. Expression of SEMA4D and its receptor PlexinB1 were also evaluated in spatial context and cellular co-localization. In summary, SEMA4D represents a novel target to regulate immune infiltration and mesenchymal suppression, sources of resistance to current immunotherapies. Pepinemab treatment was well tolerated in a Phase I oncology trial (NCT01313065) and is currently being evaluated as single agent or in ICI combinations in: (i) a Phase 1b/2a combination trial of pepinemab with avelumab in ICI naïve or ICI refractory NSCLC (CLASSICAL-Lung) (NCT03268057); (ii) a phase 1 combination trial of pepinemab with nivolumab or ipilimumab in melanoma patients who have progressed on any anti-PD-1/PD-L1 (NCT03425461); (iii) a neoadjuvant integrated biomarker trial in patients with metastatic colorectal, pancreatic (NCT03373188) and head and neck (NCT03690986) cancers treated with pepinemab in combination with nivolumab or ipilimumab; and (iv) a Phase 1/2 trial of pepinemab in children with solid tumors and children and young adults with osteosarcoma (NCT03320330). Clinical trials will evaluate safety, tolerability, efficacy, and biological endpoints, including immunophenotyping tumors and blood. Citation Format: Elizabeth E. Evans, Terrence L. Fisher, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Desa Rae Pastore, Maria Scrivens, Alan Howell, Leslie Balch, John E. Leonard, Clint Allen, Paul E. Clavijo, Gregory Lesinski, Christina Wu, Conor Steuer, Nabil F. Saba, Brian Olson, Siwen Hu-Lieskovan, Antoni Ribas, Emily G. Greengard, Ernest S. Smith, Maurice Zauderer. Altered myeloid and lymphoid composition of tumor microenvironment following anti-SEMA4D and immune checkpoint combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1545.