Exciting new cancer immunotherapies are evolving that can harness the patient’s own immune system to specifically eliminate disease. Pepinemab (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 pepinemab (VX15/2503) anti-Semaphorin 4D (SEMA4D) antibody in 42 adult patients with advanced solid tumors. In total, 460 doses of pepinemab (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. Pepinemab (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. These results were published in Clinical Cancer Research.
Four oncology studies will evaluate the safety and efficacy of pepinemab (VX15/2503).
Vaccinex is currently evaluating pepinemab (VX15/2503) in combination with Bavencio® (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). The trial is being conducted under a clinical collaboration agreement announced in 2016 between Vaccinex and 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. The design of the trial consists of a dose escalation phase for immunotherapy naïve patients who have either progressed on cytotoxic chemotherapy or declined standard first-line treatment with cytotoxic chemotherapy and have not previously received immunotherapy, to determine the recommended Phase II dose of pepinemab (VX15/2503) in combination with avelumab. This will be followed by an expansion phase for patients that are immunotherapy naïve or have progressed on standard of care immunotherapy and will enroll up to a total of 62 patients with NSCLC.
Link to ClinicalTrials.gov Identifier: NCT03268057
A study managed by the Children’s Oncology Group and NCI, was initiated in January 2018. This study is entitled: A Phase 1/2 Study of VX15 (IND#136181) in Children, Adolescents, or Young Adults with Recurrent or Relapsed Solid Tumors. The study will enroll children with advanced solid tumors and adolescents/young adults with osteosarcoma. The design of the trial consists of a dose escalation phase to determine the recommended Phase II dose of pepinemab (VX15/2503) in pediatric patients, followed by an expansion phase to enroll up to a total of 37 patients with osteosarcoma.
Link to ClinicalTrials.gov Identifier: NCT03320330
A study managed by clinicians at Winship Cancer Institute of Emory University was initiated in December 2017. This study is entitled ”Phase I Integrated Biomarker Trial of VX15 in Combination with Ipilimumab or Nivolumab in Patients with Pancreatic or Colorectal Cancer”.
This neoadjuvant “window of opportunity” study consists of four treatment groups: standard of care (no treatment), pepinemab (VX15/2503) alone, or pepinemab (VX15/2503) in combination with either ipilimumab (1 mg/kg) or nivolumab (480 mg). Enrolled patients will be treated once, on study day 1; patients will undergo surgery to resect the tumors between study day 22 and 36. Approximately 16 pancreatic cancer patients and 16 colorectal cancer patients will be enrolled in the study with 4 patients randomly assigned to each treatment group. The purpose of the study is to evaluate peripheral and tumor-infiltrating immune responses, both before and after treatment.
Link to ClinicalTrials.gov Identifier: NCT03373188
A clinical study managed by clinicians at the University of California, Los Angeles was initiated in June 2018. This study is 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”.
This study will enroll melanoma patients who have progressed on previous therapies and is intended to determine the safety and tolerability of the combination of pepinemab (VX15/2503) plus either ipilimumab or nivolumab. Patients will be randomized to receive escalating doses of pepinemab (VX15/2503) in combination with either nivolumab, administered at a dose of 400 mg once monthly, or ipilimumab, administered at a dose of 3 mg/kg every three weeks for a total of four infusions. A total of up to 60 patients will be enrolled in this study.
Link to ClinicalTrials.gov Identifier: NCT03425461
Mechanism of Action:
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 inflammatory and tumor cells regulates the infiltration, spatial distribution, and activity of myeloid cells and lymphocytes. Antibody blockade of SEMA4D delays tumor growth and promotes durable tumor rejection in preclinical melanoma, colon, breast, and head & neck cancer models. In this setting, anti-tumor activity is associated with an increase in activated antigen presenting cells, a reduction in myeloid derived suppressor cells, a shift toward a pro-inflammatory cytokine milieu, and an increase in the ratio of effector to regulatory T cells within the tumor.
We believe that combinations of anti-SEMA4D antibody with immune checkpoint inhibitors, anti-CTLA-4 anti-PD-1, anti-LAG3, or other immunomodulatory therapies and epigenetic modulators, in particular, entinostat or 5-azacytidine, may further enhance efficacy and tumor rejection in animal tumor models. 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.
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).