Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 are broadly expressed in cancer and expression correlates with invasive disease in several human tumors. SEMA4D normally functions to regulate the motility and differentiation of multiple cell types, including those of the immune, vascular, and nervous systems. In the setting of cancer, effects on cellular movement mediated by SEMA4D/PLXNB1 interactions have been described in relation to vascular stabilization and transactivation of ERBB2. Herein, we describe a novel function of SEMA4D in regulation of immune cell infiltration and activity in the tumor microenvironment (TME).

PURPOSE: Characterize immune-related and anti-tumor activity mediated by antibody neutralization of SEMA4D, as a single agent or in combination with other immunomodulatory therapies.

METHODS: Blockade of SEMA4D with monoclonal murine antibody was evaluated in subcutaneous Colon26 and orthotopic ERBB2+ breast carcinoma syngeneic models. Growth kinetics were assessed following selective in vivo immune cell depletions. Anti-tumor immune response was characterized by immunohistochemistry, FACS, and functional assays.

RESULTS: Strong expression of SEMA4D at the invasive margins of actively growing tumors modulates the infiltration and spatial distribution of leukocytes in the TME. Antibody neutralization of SEMA4D disrupts this gradient and enhances recruitment of activated antigen presenting cells and lymphocytes into the TME, shifting the balance of cytokines toward increased Th1 and reduced immunosuppressive cytokines. This orchestrated change in the tumor architecture was associated with durable tumor rejection and immunologic memory in Colon26 and ERBB2+ mammary carcinoma models. Efficacy was dependent on both active adaptive and innate immune cell responses. The immunomodulatory activity of anti-SEMA4D antibody can be enhanced by combination with other immunotherapies, including immune checkpoint inhibition and chemotherapy. Strikingly, the combination of anti-SEMA4D antibody with antibody to CTLA-4 acts synergistically to promote complete tumor rejection and survival, with significant 58% increase in tumor regression and >295% increase in survival, as compared to monotherapy.

CONCLUSION: Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the tumor and inhibit tumor progression. Humanized anti-SEMA4D therapeutic antibody, VX15/2503, has completed a Phase I prospective multiple ascending dose trial in 42 adult patients with advanced refractory solid tumors, in which the highest doses were well tolerated. Patients with the longest duration of treatment, 48-55 weeks, included colorectal, breast, and a papillary thyroid patient, who had a partial response by RECIST. A phase 1b/2a trial of combination therapy is planned.

Citation Format: Elizabeth E. Evans, Holm Bussler, Sebold Torno, Crystal Mallow, Laurie A, Winters, Christine Reilly, Katya Klimatcheva, Janaki Veeraraghavan, Alan S. Jonason, Maria Scrivens, Renee Kirk, Sue Giralico, Alan Howell, John E. Leonard, Mark Paris, Terrence L. Fisher, Ernest S. Smith, Maurice Zauderer. Antibody blockade of semaphorin 4D promotes infiltration of activated tumor infiltrating leukocytes and reverses tumor growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 278. doi:10.1158/1538-7445.AM2015-278