In addition to its association with a number of neurological disorders, SEMA4D is expressed by many tumor cells as well as by other cells in the tumor microenvironment. In fact, evidence suggests that SEMA4D expression is correlated with tumor aggression and poor prognosis in cancer patients and appears to block immune cell infiltration and activity in tumors.
Preclinical testing of pepinemab, a monoclonal antibody inhibitor of SEMA4D, has demonstrated immune cell-dependent, anti-tumor activity in mouse models, characterized by an increase in CD8+ and decrease in inhibitory FoxP3+ T-cells and myeloid derived suppressor cells (MDSC) post-treatment. Vaccinex has acted on this preclinical validation of pepinimab’s potential for treatment in cancer and initiated a phase 1b/2 trial in combination with Merck KGaA’s antiPD-L1 checkpoint inhibitor, BAVENCIO® (avelumab).
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 fail to penetrate tumor in the negative control.
SEMA4D is broadly expressed in many human cancers, and its expression correlates with invasive human disease. SEMA4D regulates the movement and differentiation of immune and vascular cells in the tumor environment. Antibody blockade of SEMA4D increases immune infiltration and activity in tumors and promotes durable tumor rejection in preclinical melanoma, colon, breast, and head & neck cancer models.
Preclinical studies demonstrated high concentrations of SEMA4D expressed at the growing edge, the invasive margin of tumors which serves to immobilize immune cells and restrict infiltration.. Antibodies against SEMA4D neutralize this barrier and “open the gates” of the tumor to the immune system. This facilitates anti-tumor immune responses and results in reduced tumor burden in animals.
Administration of anti-SEMA4D antibody changes the tumor microenvironment by increasing infiltration of many types of immune cells that orchestrate a complex response. This results not only in greatly increasing the number of immune killer cells that can attack the tumor, it also reduces the production of immunosuppressive cells that could otherwise interfere with this activity. Because they need to overcome the first line of defense against cancer, the protective immune system, tiumors employ multiple immune evasion mechanisms. In addition to SEMA4D associated mechanisms, it is now well known that tumors express checkpoints like PD-L1 that can prevent activation of immune cells by binding to their matching PD-1 receptors. Checkpoint inhibitors have been developed to block the PD-1/PD-L1 signaling pathway. It is expected that an effective cancer treatment will likely need to overcome all these tumor defenses. We, therefore, investigated the use of SEMA4D blocking antibody in combination with a checkpoint inhibitor. We detected strong synergy between the two anti-cancer agents. Optimal activity was observed when animals were treated with the combination of anti-SEMA4D antibody and a checkpoint inhibitor.
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, TAM – Tumor associated macrophage)
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 pepinemab (VX15/2503) acts synergistically to reduce immunosuppression and “open the gates” of the tumor to immune infiltration. More data is available in Evans, et al. Cancer Immunology Research (link above).
Vaccinex has successfully completed a two-center Phase I, multiple ascending dose clinical trial of pepinemab in 42 adult patients with advanced solid tumors. Pepinemab was found to be well tolerated at the highest dose level tested, 20 mg/kg.
Studies of pepinemab in cancer extend beyond just those being conducted by Vaccinex. In total, six oncology studies will evaluate the safety and efficacy of pepinemab.
Study 1: Vaccinex is close to completing a study of pepinemab in combination with avelumab, a human anti-PD-L1 IgG1 monoclonal antibody, in a Phase Ib/II study in patients with advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC) in a clinical collaboration with Merck KGaA, Darmstadt, Germany. The clinical trial, short-named “CLASSICAL – Lung”, is a multi-center, open-label study designed to evaluate the safety and potential efficacy of the combination of pepinemab (VX15/2503) and avelumab in patients with advanced NSCLC.
Intrim results of this study have been reported. In both patients that have not previously received immunotherapy and those that had been treated but whose tumors progressed following treatment with single-agent checkpoint inhibitor, increased CD8+ cytotoxic T cell activity and either reduction or stabilization of tumor burden was observed in a majority of patients. The objective responses for patients that received the combination treatment appeared to be 2 to 2.5 times higher than those for a comparable population of patients who received single agent Bavencio® (avelumab) in a prior study. Progression-free survival also appeared to be extended by combination therapy.
A study managed by the Children’s Oncology Group and NCI, entitled A Phase 1/2 Study of VX15 (IND#136181) in Children, Adolescents, or Young Adults with Recurrent or Relapsed Solid Tumors, enrolled children with advanced solid tumors and adolescents/young adults with osteosarcoma for treatment with single agent pipinemab. The trial was initiated in January 2018 and was completed in April 2020.
Link to ClinicalTrials.gov Identifier: NCT03320330
Study 3, 4 and 5.
Three Investigator Sponsored Studies (IST) are being managed by clinicians at the Winship Cancer Institute of Emory University to evaluate the effect of diverse treatment regimens including pepinemab on the immune profile in the tumor microenvironment.
- Study 3: A Phase 1 clinical trial evaluating pepinemab (VX15/2503) as a single agent and in combination with ipilimumab or nivolumab in pre-surgical patients with resectable pancreatic and colorectal cancer. Link to ClinicalTrials.gov Identifier: NCT03373188
- Study 4: A Phase 1 clinical trial evaluating pepinemab as a single agent and in combination with ipilimumab or nivolumab in pre-surgical patients with resectable head and neck cancer. Link to ClinicalTrials.gov Identifier: NCT03690986
- Study 5: A Phase 1 clinical trial evaluating pepinemab as a single agent and in combination with ipilimumab or nivolumab in pre-surgical patients with resectable melanoma. Link to ClinicalTrials.gov Identifier: NCT03769155
A clinical study managed by clinicians at the University of California, Los Angeles entitled “Phase I Study Combining an Anti-SEMA4D Antibody VX15/2503 with Checkpoint Inhibitors for Patients With Advanced Melanoma Who Have Progressed on Prior Anti-PD1/L1 Based Therapies,” is intended to determine the safety and tolerability of the combination of pepinemab (VX15/2503) plus either ipilimumab or nivolumab.The study was initiated in June 2018.
Link to ClinicalTrials.gov Identifier: NCT03425461