Abstract 1762: Shifting the tumor microenvironment with first-in-class semaphorin 4D mab for combination immunotherapy
Authors: Evans Elizabeth E. , Bussler Holm , Mallow Crystal , Reilly Christine , Torno Sebold , Scrivens Maria , Howell Alan , Balch Leslie , Leonard John E. , Fisher Terrence , Allen Clint , Clavijo Paul E. , Lesinski Gregory , Wu Christina , Hu-Lieskovan Siwen , Ribas Antoni , Greengard Emily G. , Smith Ernest S. , Zauderer Maurice 
Published: August 2018

Abstract
Purpose: In preclinical models, tumor growth inhibition by anti-semaphorin 4D (SEMA4D, CD100) blocking antibody is enhanced when combined with various immunotherapies. Immune checkpoint combinations with humanized VX15/2503 anti-SEMA4D are currently being evaluated in several clinical trials. Methods: Expanded mechanistic studies in preclinical models investigate the effect of SEMA4D signaling through its Plexin receptors (PLXN) on MDSC function and chemokine secretion in the tumor microenvironment. Humanized VX15/2503 anti-SEMA4D is now also being evaluated as single agent or in combination with other immunotherapies in four clinical trials:: (i) a Phase 1b/2a combination trial of VX15/2503 with avelumab in NSCLC (CLASSICAL-Lung); (ii) a phase 1 combination trial with nivolumab or ipilimumab in melanoma patients who have progressed on any anti-PD-1/PD-L1; (iii) a neoadjuvant integrated biomarker trial in patients with metastatic colorectal and pancreatic cancers treated with VX15/2503 in combination with nivolumab or ipilimumab; and (iv) a Phase 1/2 trial of VX15/2503 in children with solid tumors and children and young adults with osteosarcoma. Results: SEMA4D plays a multi-faceted role within the tumor microenvironment by creating a barrier at the tumor-stroma margin to restrict immune cell infiltration and promoting immunosuppressive activity of myeloid-derived cells. SEMA4D directly enhanced ability of MDSC to suppress T cell proliferation and antibody blockade reversed these effects, both in vitro and in vivo. Furthermore, SEMA4D-PLXN signaling modulates expression of chemokines that recruit MDSC. Importantly, anti-SEMA4D MAb can enhance activity of co-administered immunotherapies in murine colon, head and neck (HNSCC), and melanoma models. For example, anti-SEMA4D plus anti-CTLA-4 results in 100% survival and 90% complete tumor rejection (CR) (p&lt;0.0001) in an HNSCC model representative of a T cell inflamed tumor with high MDSC suppression. Entinostat has broad immunomodulatory effects, including reduction of MDSC, and combination treatment of established Colon26 tumors with anti-SEMA4D and entinostat results in maximal tumor growth delay and 90% CR (p&lt;0.0001). Conclusions: SEMA4D blockade represents a novel approach to promote functional immune infiltration into the tumor, reduce mesenchymal suppression, and enhance immunotherapy. VX15/2503 treatment was well tolerated in a Phase I trial in patients with advanced refractory solid tumors. Several clinical trials are in progress to evaluate safety, tolerability, efficacy, and biological endpoints, including immunophenotyping tumors and blood of patients treated with VX15/2503 in combination with immune checkpoint antibodies. Finally, a pediatric phase 1/2 trial based on the previously described role of SEMA4D as an oncogene in osteosarcoma and its immunomodulatory effects is being conducted.
Citation Format: Elizabeth E. Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Alan Howell, Leslie Balch, John E. Leonard, Terrence Fisher, Clint Allen, Paul E. Clavijo, Gregory Lesinski, Christina Wu, Siwen Hu-Lieskovan, Antoni Ribas, Emily G. Greengard, Ernest S. Smith, Maurice Zauderer. Shifting the tumor microenvironment with first-in-class semaphorin 4D mab for combination immunotherapy [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 1762.