Semaphorin 4D (SEMA4D, CD100) and its receptor plexin-B1 are broadly expressed in cancer and expression correlates with invasive disease in several human tumors. We have reported a novel role for SEMA4D in modulating the tumor microenvironment (TME) to exclude activated antigen presenting cells and cytotoxic T lymphocytes so as to promote tumor growth; this effect can be reversed by antibody blockade.
Purpose: Characterize immune-related anti-tumor activity mediated by antibody neutralization of SEMA4D, as a single agent and in combination with other immunomodulatory therapies, including immune checkpoint inhibition.
Methods: Blockade of SEMA4D with monoclonal murine antibody was evaluated in murine melanoma and colon cancer models. Immune response in pre-clinical models was characterized by immunohistochemistry, flow cytometry, functional assays, as well as cytokine, chemokine and gene expression analysis. Therapeutic activity was evaluated in various preclinical models. A Phase I trial in patients with advanced solid tumors was completed.
Results: SEMA4D restricts migration of macrophage cell lines and promotes expansion of suppressive tumor associated macrophage (TAM) and myeloid derived suppressor cells (MDSC) in vitro. Strong expression of SEMA4D at the invasive margins of actively growing tumors in vivo modulates the infiltration and polarization of leukocytes in the TME. In preclinical models, antibody neutralization disrupted the SEMA4D gradient at the invasive margin, which correlated with recruitment of activated APCs and T lymphocytes into the TME. This was accompanied by a significant shift towards increased Th1 cytokines (IFNΓ, TNFA) and CTL-recruiting CXCL9 chemokine, with concurrent reduction in Treg-, MDSC- and M2-macrophage promoting chemokines (CCL2, CXCL1, CXCL5). Accordingly, an increase in Teff:Treg ratio (3x, p<0.005) and CTL activity (4x, p<0.0001) was observed. MDSCs were significantly reduced in both tumor and blood following treatment. Nanostring gene expression analysis of on-treatment tumors confirms an increase in the gamma-inflammatory immune gene signature that was predictive of ORR and PFS in KEYNOTE 001 (Ribas, ASCO 2015), including significant increases in CXCL9, Gzmb, CCR5, Stat1, Lag3, Ptprc (NK function), Ciita (MHC presentation), Pdcd1 (PD-1), Itga1 (adhesion, leukocyte function). The coordinated anti-SEMA4D induced changes in the tumoral immune context are associated with durable tumor rejection and immunologic memory in preclinical colon, breast, and melanoma models. Importantly, the immunomodulatory activity of anti-SEMA4D antibody can be further enhanced by combination with other immunotherapies, including immune checkpoint inhibitors and chemotherapy. Strikingly, the combination of anti-SEMA4D with anti-CTLA-4 acts synergistically, with maximal increase in survival (110% tumor growth delay, p<0.01) and complete tumor regression in 100% of mice, as compared to 22% with monotherapy (p<0.01). SEMA4D antibody treatment was well tolerated in nonclinical and clinical studies; including a Phase I multiple ascending dose trial in patients with advanced refractory solid tumors. 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. Progression free survival strongly correlated with elevated baseline lymphocyte counts (r = 0.6133), consistent with an immune mediated mechanism of action for VX15/2503, a humanized IgG4 anti-SEMA4D antibody.
Conclusion: Inhibition of SEMA4D represents a novel mechanism and therapeutic strategy to promote functional immune infiltration into the tumor and inhibit tumor progression. Phase 1b/2a trials of combination therapy with immune checkpoint inhibition are planned.
Citation Format: Elizabeth E. Evans, Holm Bussler, Crystal Mallow, Christine Reilly, Sebold Torno, Ekaterina Klimatcheva, Maria Scrivens, Cathie Foster, Alan Howell, Leslie Balch, Alyssa Knapp, John E. Leonard, Mark J. Paris, Terrence L. Fisher, Siwen Hu-Lieskovan, Antoni Ribas, Ernest S. Smith, Maurice Zauderer. Antibody blockade of Semaphorin 4D enhances infiltration of APC and CD8 T cells and reduces immune suppression to facilitate immune-mediated tumor rejection [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B023.
- ©2016 American Association for Cancer Research.