Abstract 4888: Antibody blockade of semaphorin 4D breaks down stromal barriers to enhance tumoricidal immune infiltration, supporting rational immunotherapy combinations

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-07, Vol.76 (14_Supplement), p.4888-4888
• Main Authors: Evans, Elizabeth E., Bussler, Holm, Torno, Sebold, Mallow, Crystal, Reilly, Christine, Scrivens, Maria, Klimatcheva, Ekaterina, Winter, Laurie A., Kirk, Renee, Howell, Alan, Balch, Leslie, Leonard, John E., Paris, Mark, Fisher, Terrence L., Hu-Lieskovan, Siwen, Ribas, Antoni, Smith, Ernest S., Zauderer, Maurice
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2016-4888

Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 are broadly expressed in cancer; increased expression correlates with poor prognosis. SEMA4D normally functions to regulate the motility and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. In the tumor microenvironment (TME), SEMA4D is expressed strongly at the invasive margin and modulates the infiltration and spatial distribution of leukocytes, suppressing anti-tumor activity. Neutralization of SEMA4D was evaluated for effects on immune activity and tumor growth in preclinical models, incorporating single agent and combination treatments with other immunotherapies, including immune checkpoint blockade inhibitors. The safety and tolerability of humanized anti-SEMA4D antibody VX15/2503 was assessed in a Phase I clinical trial. RESULTS: SEMA4D restricts migration of myeloid cells expressing cognate PLXNB1/2 receptors, determined using trans-well migration assays and IHC of in vivo tumors. Antibody neutralization disrupted the SEMA4D gradient at the invasive margin, which correlated with recruitment of activated APCs and T lymphocytes into the TME, and significant shift toward increased Th1 cytokines (IFNg, TNFa) and CTL-recruiting CXCL9 chemokine, with concurrent reduction in Treg- and M2-macrophage promoting chemokines (CCL2, CXCL1, CCL17). Accordingly, an increase in Teff:Treg ratio (3x, p