Abstract 3661: Breaking down the barrier restricting infiltration and differentiation of APC in the tumor microenvironment with a first-in-class antibody targeting Semaphorin4D, and rational combination therapies
Authors: Evans Elizabeth E. , Bussler Holm , Mallow Crystal , Reilly Christine , Torno Sebold , Scrivens Maria , Foster Cathie , Howell Alan , Comeau Stephen R. , Balch Leslie , Knapp Alyssa , Leonard John E. , Fisher Terrence L. , Hu-Lieskovan Siwen , Ribas Antoni , Smith Ernest S. , Zauderer Maurice 
Published: July 2017

Abstract
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 1b/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. Anti-tumor 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. M-MDSCs were significantly reduced in tumor and blood following treatment. A significant shift towards increased Th1 cytokines (IFNγ, TNFα) and CTL-recruiting chemokine CXCL9, with concurrent reduction in Treg-, MDSC- and M2-macrophage promoting chemokines (CCL2, CXCL1, CXCL5) was observed. Accordingly, Teff:Treg ratio (3x, p&lt;0.005) and CTL activity (4x, p&lt;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 co-administered immunotherapies and chemotherapy. For example, the combination with immune checkpoint inhibitor anti-CTLA-4 causes complete tumor regression in 100% of mice, as compared to 22% with monotherapy (p&lt;0.01). Additional studies of combinations with other immunomodulators, including treatment of established tumors with HDAC inhibitor Entinostat, will be presented.
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. Phase 1b/2 trials of combination therapy with avelumab in NSCLC patients who are immunotherapy naïve, and combinations with anti- anti-PD-1 and/or anti-CTLA-4 in melanoma and HNSCC patients who are refractory to PD1 inhibitors are planned in 2017.
Citation Format: Elizabeth E. Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Maria Scrivens, Cathie Foster, Alan Howell, Stephen R. Comeau, Leslie Balch, Alyssa Knapp, John E. Leonard, Terrence L. Fisher, Siwen Hu-Lieskovan, Antoni Ribas, Ernest S. Smith, Maurice Zauderer. Breaking down the barrier restricting infiltration and differentiation of APC in the tumor microenvironment with a first-in-class antibody targeting Semaphorin4D, and rational combination therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3661. doi:10.1158/1538-7445.AM2017-3661