Abstract PR10: Reprogramming myeloid cells in TME with pepinemab, first-in-class semaphorin 4D MAb, enhances 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 L. , Allen Clint , Clavijo Paul , Lesiniski Gregory , Wu Christina , Hu-Lieskovan Siwen , Ribas Antoni , Greengard Emily , Smith Ernest S. , Zauderer Maurice 
Published: February 2019

Abstract
Purpose: Tumor growth inhibition by anti-semaphorin 4D (SEMA4D, CD100) blocking antibody is enhanced when combined with various immunotherapies in preclinical animal models. Immune checkpoint combinations with pepinemab (VX15/2503), a humanized anti-SEMA4D antibody, are currently being evaluated in several clinical trials. Methods: Expanded mechanistic studies in syngeneic preclinical models investigated the effect of SEMA4D blockade on immune contexture within the tumor microenvironment, as a single agent and in combination with various immunotherapy agents. Antitumor activity and immune response was characterized by immunohistochemistry, flow cytometry, functional assays, and cytokine, chemokine and gene expression analysis. Pepinemab (VX15/2503) is currently being evaluated as single agent or in combination with other immunotherapies in four clinical trials: (i) a phase 1b/2a combination trial of pepinemab with avelumab in 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 (NCT03373188); (iii) a neoadjuvant integrated biomarker trial in patients with metastatic colorectal and pancreatic cancers treated with pepinemab in combination with nivolumab or ipilimumab (NCT03373188); and (iv) a phase 1/2 trial of pepinemab in children with solid tumors and children and young adults with osteosarcoma (NCT03320330). Results: SEMA4D exerts multifaceted effects 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. Blocking antibody to SEMA4D directly enhanced M1/M2 ratio and both reduced expression of chemokines that recruit MDSC and the ability of MDSC to suppress T-cell proliferation. Antibody blockade reduced the function of immunosuppressive myeloid and regulatory T-cells in the TME while simultaneously restoring the ability of dendritic cells and cytotoxic T-cells to migrate into the tumor in several syngeneic tumor models. Importantly, anti-SEMA4D MAb enhanced the activity of co-administered immunotherapies in murine colon, head and neck (HNSCC), and melanoma models. For example, anti-SEMA4D plus anti-CTLA-4 resulted 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 suppressive function, and combination treatment of established Colon26 tumors with anti-SEMA4D and entinostat resulted 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 effects. Pepinemab treatment was well tolerated in a phase I trial in patients with advanced refractory solid tumors (NCT01313065, Patnaik A et al., Clin Cancer Res 2016;22(4):827-36). Several clinical trials are in progress to evaluate safety, tolerability, efficacy, and biologic endpoints, including immunophenotyping tumors and blood of patients treated with pepinemab in combination with immunomodulatory agents. Finally, a pediatric phase 1/2 trial is being conducted based on the previously described role of SEMA4D as an oncogene in osteosarcoma and its immunomodulatory effects.
Citation Format: Elizabeth E. Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Alan Howell, Leslie Balch, John E. Leonard, Terrence L. Fisher, Clint Allen, Paul Clavijo, Gregory Lesiniski, Christina Wu, Siwen Hu-Lieskovan, Antoni Ribas, Emily Greengard, Ernest S. Smith, Maurice Zauderer. Reprogramming myeloid cells in TME with pepinemab, first-in-class semaphorin 4D MAb, enhances combination immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr PR10.