Antibody blockade of semaphorin 4D promotes infiltration of activated tumor infiltrating leukocytes and inhibits tumor growth. (TUM7P.1030)

• Published in: The Journal of immunology (1950) 2015-05, Vol.194 (1_Supplement), p.142-142.19
• Main Authors: Klimatcheva, Ekaterina, Evans, Elizabeth, Bussler, Holm, Torno, Sebold, Mallow, Crystal, Winter, Laurie, Reilly, Christine, Veeraraghavan, Janaki, Jonason, Alan S., Scrivens, Maria, Kirk, Renee, Giralico, Susan, Howell, Alan, Leonard, John, Paris, Mark, Fisher, Terrence, Smith, Ernest, Zauderer, Maurice
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.194.Supp.142.19

Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 are broadly expressed in cancer and expression correlates with invasive disease. A novel function of SEMA4D, regulating immune cell infiltration and activity in the tumor microenvironment (TME), is described. Antibody neutralization of SEMA4D enhances recruitment of activated antigen presenting cells and lymphocytes into the TME, shifting the balance of cells and cytokines toward increased Th1 and reduced immunosuppression. This orchestrated change in the tumor architecture was associated with durable tumor rejection and immunologic memory in several syngeneic tumor models. The immunomodulatory activity can be enhanced by combination with other immunotherapies. Strikingly, in some models, the combination of anti-SEMA4D antibody with immune checkpoint blockade acts synergistically to reverse tumor growth. Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the tumor and inhibit tumor progression. A humanized 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.