Semaphorin 4D (SEMA4D, CD100) 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, SEMA4D promotes tumor progression and metastasis. SEMA4D and its receptor plexin B1 are broadly expressed in murine and human tumors; expression correlates with invasive disease in several human tumors. SEMA4D is highly expressed on T cells and is also released as a biologically active soluble molecule by activated inflammatory cells. Preclinical studies demonstrate a novel immunomodulatory function of SEMA4D, whereby SEMA4D influences the recruitment and distribution of leukocytes in the tumor microenvironment. Antibody blockade of SEMA4D with the murine progenitor of VX15/2503 regulates the balance and activity of inflammatory and tolerance-inducing cells and cytokines to effectively delay tumor growth and promote durable tumor rejection in syngeneic colon and breast cancer models. Combination of anti-SEMA4D antibody with immune checkpoint inhibitor anti-CTLA-4 enhances anti-tumor immune activity and synergistically increases tumor rejection. Combinations with anti-PD-1 or cyclophosphamide, an immunomodulatory chemotherapy reported to differentially affect regulatory T cells, also increases efficacy and frequency of tumor rejection. Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote immune infiltration and distribution in the tumor microenvironment and inhibit tumor progression.
The humanized anti-SEMA4D antibody, VX15/2503, has successfully completed a Phase I multiple ascending dose trial in adult patients with advanced refractory solid tumors. Patients were administered weekly IV doses of VX15/2503 until progression. Dose levels were 0.3 to 20 mg/kg. Tumors were assessed by RECIST 1.1 after each 8 dose cycle.
The study has concluded (n=42 Pts); sex 40%M/60%F. Mean age (yrs) 64.8; ECOG 0/1/2 are 28.6%/69%/2.4%. No MTD was found. One DLT (grade 3 GGT elevation; 15 mg/kg) was reported in a pancreatic cancer patient with disease progression. The most frequent treatment-related AE's (n=42 pts) included grade 1/2 nausea (14.3%) and fatigue (11.9%) and 15 unrelated SAE's were reported in 12 patients. Thirteen of 42 pts at all dose levels exhibited stable disease for at least 8 weeks. Patients with the longest duration of treatment, 48-55 weeks, included colorectal (9 mg/kg); breast (15 mg/kg); and papillary thyroid (20 mg/kg)—this patient had a partial response by RECIST and stable disease for at least 6 months following cessation of treatment at 48 weeks. VX15/2503 serum concentrations of ≥ 0.3 µg/mL produced complete saturation of membrane SEMA4D on circulating T cells. HAHA responses (titer > 100) with possible effects on PK were observed in 4 of 41 patients (10%); in only 1 patient (2%) was an effect of HAHA on PD observed.
VX15/2503 was well tolerated at dose levels up to 20 mg/kg, with 459 doses administered to 42 patients. A phase 1b/2a trial of combination therapy with anti-CTLA-4 is planned.
Citation Format: Elizabeth E. Evans, Terrence L. Fisher, Cynthia Edington, Holm Bussler, Sebold Torno, Alan S. Jonason, Jr., Janaki Veeraraghavan, Christine Reilly, Michael A. Doherty, Jennifer Seils, Laurie A. Winter, Tracy Pandina, Crystal Mallow, Renee Kirk, Alan Howell, Sue Giralico, Maria Scrivens, Katya Klimatcheva, William J. Bowers, Mark Paris, Drew Warren Rasco, Ramesh K. Ramanathan, Amita Patnaik, Glen J. Weiss, Danielle Mutz, Lisa Blaydorn, Anthony W. Tolcher, Valerie Iddison, Ernest S. Smith, John E. Leonard, Maurice Zauderer. Phase 1 study of VX15/2503, an immunomodulatory antibody to Semaphorin 4D that reverses tumor growth in preclinical studies. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A67.
- ©2015 American Association for Cancer Research.