Abstract 5030: Antibody blockade of Semaphorin 4D promotes tumor rejection and improves response to immune checkpoint blockade and chemotherapy
Authors: Evans Elizabeth E. , Bussler Holm , Torno Sebold , Veeraraghavan Janaki , Jonason Alan S. , Doherty Michael A. , Reilly Christine , Mallow Crystal , Seils Jennifer , Paris Mark , Fisher Terrence L. , Bowers William J. , Scrivens Maria , Balch Leslie , Kirk Renee , Howell Alan , Iddison Valerie , Leonard John E. , Smith Ernest S. , Zauderer Maurice 
Published: May 2015

Abstract
Semaphorin4D (SEMA4D) normally functions to regulate, adhesion, motility and activation state of multiple cell types including those of the nervous, vascular and immune systems. In the setting of cancer, SEMA4D has been shown to promote tumor progression and metastasis. SEMA4D and its high affinity receptor plexin B1 are broadly expressed in human and murine tumors, and expression levels correlate with invasive disease in several human tumors. The interaction of plexin B1 with MET and ERBB2 can lead to SEMA4D-mediated transactivation of these membrane receptor kinases with a direct effect on tumor cell migration and invasive growth. Moreover, SEMA4D is highly expressed by inflammatory cells that are recruited to the tumor microenvironment.
Purpose: Determine the role(s) of SEMA4D in shaping the tumor microenvironment, and investigate the anti-tumor response mediated by antibody neutralization of SEMA4D as a single agent or in combination with other immunomodulatory therapies.
Methods: Subcutaneous colon and orthotopic ERBB2+ breast carcinoma models were employed to investigate treatment with a monoclonal antibody to SEMA4D. Anti-tumor response and tumor infiltrating immune cell profiles were characterized by in vivo growth kinetics, immunohistochemistry, FACS, and functional assays.
Results: We describe an immunomodulatory function of SEMA4D within the tumor microenvironment, whereby SEMA4D influences the recruitment and activity of cytotoxic CD8+ T cells, the density of B cells within the tumor, and regulates the balance and localization of inflammatory M1 and tolerance-inducing M2 macrophage in tumor stroma. Antibody blockade of SEMA4D modifies the balance of immune cells and production of pro-inflammatory cytokines within the tumor microenvironment, promotes tumor rejection, and induces ∼30% tumor growth delay (TGD) in Colon26 and &gt;70% TGD in Tubo breast tumor models. Furthermore, combination of SEMA4D antibody with immune checkpoint blockade inhibitor antibodies to CTLA4 and PD1, significantly improves frequency of complete tumor rejection (58% and 37%) and increases survival (&gt;295% and &gt;55% TGD respectively) as compared to monotherapy with these targeted agents. Similar combinatorial effects were observed when anti-SEMA4D antibody is administered with immunomodulatory chemotherapy, such as cyclophosphamide, which increases efficacy (81% TGD) and frequency of complete rejection (40%) in tumor engrafted mice.
Conclusion: SEMA4D represents a novel immunological target and antibody neutralization of SEMA4D may be a novel therapeutic option for cancer treatment. The humanized anti-SEMA4D antibody, VX15/2503, has successfully completed IND-enabling toxicology testing and the dose escalation phase of a Phase I trial, in which the highest doses were well tolerated in adult patients with advanced solid tumors.
Citation Format: Elizabeth E. Evans, Holm Bussler, Sebold Torno, Janaki Veeraraghavan, Alan S. Jonason, Michael A. Doherty, Christine Reilly, Crystal Mallow, Jennifer Seils, Mark Paris, Terrence L. Fisher, William J. Bowers, Maria Scrivens, Leslie Balch, Renee Kirk, Alan Howell, Valerie Iddison, John E. Leonard, Ernest S. Smith, Maurice Zauderer. Antibody blockade of Semaphorin 4D promotes tumor rejection and improves response to immune checkpoint blockade and chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5030. doi:10.1158/1538-7445.AM2014-5030