Purpose: We expand mechanistic findings in preclinical studies to demonstrate that antibody blockade of semaphorin 4D (SEMA4D, CD100) reduces expansion of MDSC and shifts the balance of myeloid cells within the TME to facilitate tumor rejection. Efficacy is further enhanced when combined with various immunotherapies. Design of phase 1/2 combination trials of VX15/2503, a humanized IgG4 antibody targeting SEMA4D, with immune checkpoint inhibition will be presented.
Methods: Anti-SEMA4D antibodies were evaluated alone and in combination with other immunotherapies in various preclinical models. Antitumor activity and immune response was characterized by immunohistochemistry, flow cytometry, functional assays, and cytokine, chemokine, and gene expression analysis. A phase I trial for single agent VX15/2503 was completed, and several 1b/2 combination immunotherapy trials are planned.
Results: SEMA4D restricts migration of monocytes and promotes expansion of suppressive myeloid cells in vitro. Strong expression of SEMA4D at the invasive margins of actively growing tumors in vivo restricts the infiltration and modulates polarization of leukocytes in the TME. Antibody blockade of SEMA4D facilitated recruitment of activated DCs and T lymphocytes in preclinical models. MDSCs were significantly reduced in tumor and blood following treatment, and new data characterizing MDSC function in preclinical models will be described. A significant shift towards increased Th1 cytokines (IFNg, TNFa) and CTL-recruiting chemokine CXCL9, with concurrent reduction in Treg- , MDSC- , and M2-macrophage promoting chemokines (CCL2, CXCL1, CXCL5) was also observed. Accordingly, Teff:Treg ratio (3x, p<0.005) and CTL activity (4x, p<0.0001) were increased. These coordinated changes in the tumoral immune context are associated with durable tumor rejection and immunologic memory in murine colon, breast, and melanoma models. Importantly, anti-SEMA4D treatment can further enhance activity of coadministered immunotherapies and chemotherapy. For example, combinations with immune checkpoint inhibitor anti-LAG3 or anti-CTLA-4 cause complete tumor regression in 90% or 100% of mice, as compared to ~20% with monotherapy (p<0.01). New data presented include synergistic activity of combinations of anti-SEMA4D with anti-LAG3 and additional studies of combinations with epigenetic modulators, including treatment of established tumors.
Conclusions: SEMA4D blockade represents a novel mechanism to promote functional immune infiltration into the tumor and enhance immunotherapy. VX15/2503 treatment was well tolerated in a phase I multiple ascending dose trial in patients with advanced refractory solid tumors. Plans for several clinical trials will be presented, including a phase 1b/2 of combination therapy with avelumab in immunotherapy-naïve NSCLC, and combination with anti-PD-1 or ipilimumab in various indications. A neoadjuvant trial of VX15 with anti-PD-1 in patients with metastatic colorectal and pancreatic cancers will be described, as well as a phase 1/2 trial of VX15 in pediatric and osteosarcoma patients.
This abstract is also being presented as Poster B01.
Citation Format: Elizabeth E. Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, John E. Leonard, Terrence L. Fisher, Clint Allen, Paul Clavijo, Siwen Hu-Leiskovan, Antoni Ribas, Ernest S. Smith, Maurice Zauderer. Breaking down barriers restricting myeloid cell differentiation and infiltration in the tumor microenvironment with a first-in-class antibody targeting semaphorin4D, and rational combination therapies [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr PR09.