Exciting new cancer immunotherapies are evolving that can harness the patient’s own immune system to specifically eliminate disease. VX15/2503 is a novel, immuno-modulating, monoclonal antibody that targets Semaphorin 4D (SEMA4D, CD100). Preclinical testing has demonstrated immune cell-dependent, anti-tumor activity. Vaccinex is committed to the development of this potentially important therapeutic.
Vaccinex has successfully completed a two-center Phase I, multiple ascending dose clinical trial of VX15/2503 anti-Semaphorin 4D (SEMA4D) antibody in 42 adult patients with advanced solid tumors. In total, 460 doses of VX15/2503 were administered to patients, with antibody concentration ranging from 0.3 to 20 mg/kg. Patient tumors were assessed by RECIST 1.1 at approximately 8 week intervals. VX15/2503 was found to be well tolerated at dose levels up to 20 mg/kg. Anti-tumor response was examined as an exploratory objective of the study. Seventeen of 42 patients at all dose levels exhibited stable disease for at least 8 weeks and nine patients showed stable disease for ≥ 16 weeks. 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 and stable disease for at least 6 months following cessation of treatment at 48 weeks.
Immunohistochemical staining of mice harboring colon26 tumors treated with anti-SEMA4D shows an increase in CD8+ T cells that infiltrate the interior of the tumor whereas the T cells are restricted to blood vessels and stroma in the negative control.
In preclinical studies, it was determined that a high concentration of SEMA4D is expressed at the growing invasive margin of tumors and that this restricts infiltration of anti-tumor immune cells. Antibodies against SEMA4D neutralize this barrier and “open the gates” of the tumor to the immune system. This facilitates anti-tumor immune responses and effectively reduces tumor burden in animals. In these models of cancer, administering antibodies against SEMA4D alone results in tumor growth delay and durable tumor regressions with demonstrated immunological memory. This activity can be further enhanced in combination with other effective immunotherapies, such as immune checkpoint blockade inhibitors and some chemotherapy.
SEMA4D is broadly expressed in many human cancers and its expression correlates with invasive human disease. SEMA4D normally functions to regulate the movement and differentiation of certain cells, including those of the immune and vascular systems. In the preclinical tumor microenvironment, expression of SEMA4D by activated inflammatory cells regulates the infiltration, spatial distribution, and activity of antigen presenting cells and lymphocytes. Antibody blockade of SEMA4D delays tumor growth and promotes durable tumor rejection in preclinical colon and breast cancer models. In this setting, anti-tumor activity is associated with an increase in activated antigen presenting cells, a shift toward a pro-inflammatory cytokine milieu, and an increase in the ratio of effector to regulatory T cells within the tumor.
Effects of anti-SEMA4D therapy on the cycle of cancer immunity. Key steps in the cycle of cancer immunity are shown, along with examples of therapies that can induce and/or amplify the immune response to cancer (adapted from Chen and Mellman review, Immunity 2013, 39:1). Rational combination therapies can drive the cycle toward productive anti-tumorigenic effects. Based on our pre-clinical studies, anti-SEMA4D is included as a novel mechanism to regulate immune cell migration and reduce immunosuppression within the tumor microenvironment. (APC – Antigen Presenting Cell, Treg – Regulatory T cell, CD8 – CD8+ T cell)
Combinations of anti-SEMA4D antibody with immune checkpoint inhibitors, anti-CTLA-4 and anti-PD-1, or cyclophosphamide further enhance efficacy and tumor rejection. Additional reported mechanisms of action include vascular remodeling and transactivation of oncogenic receptor tyrosine kinases, ERBB2 and Met, by SEMA4D crosslinking of PlexinB1, a high affinity receptor for SEMA4D. Inhibition of SEMA4D therefore represents a novel mechanism to promote functional immune infiltration in the tumor and inhibit tumor progression.
Vaccinex publication describing preclinical studies of anti-SEMA4D:
Evans, et al. Cancer Immunol Res. 2015 Jun;3(6):689-701 (link)
Spatial and phenotypic reorganization of antigen presenting cells in mouse colon tumors:
Colon26 tumors were collected on day 29 from Balb/c mice treated with Control IgG1 or MAb67. Serial sections were stained for expression of SEMA4D (left panel), CD11c (red) and F4/80 (green) (middle panels), merge is shown in right panel. A region of strongly SEMA4D-positive tumor and stroma was observed in Control tumors, indicated by brackets. Both SEMA4D gradient and distribution of monocytes and T cells were altered by SEMA4D blockade. Visual assessment suggests an increase in infiltration of F480+CD11c+ DCs. See Evans, et al. Cancer Immunology Research (link above) for additional details.
Results suggest synergy with anti-CTLA-4
Anti-CTLA-4 promotes expanded responses to tumor antigens in peripheral immune tissue while VX15 acts synergistically to “open the gates” of the tumor to immune infiltration. More data is available in Evans, et al. Cancer Immunology Research (link above).