pepinemab (VX15) / Vaccinex - LARVOL DELTA

Neoadjuvant pepinemab in combination with nivolumab and/or ipilimumab in resectable stage III melanoma (ESMO 2022) - P1 | "The combination of pepi/nivo/ipi provides robust pathologic response, durable response, and suitable toxicity. Analysis of biomarker endpoints is ongoing and will inform further development of this regimen."

Clinical • Combination therapy • Melanoma • Oncology • Solid Tumor

Neoadjuvant biomarker trial of pepinemab to enhance nivolumab or ipilimumab activity in resectable head and neck cancer. (ASCO 2025) - P1 | "Neoadjuvant treatment with pepi enhanced the density and maturity of TLS deep within the tumor which was most prominent in combination with nivo notably in HPV-negative disease. Pepi represents a novel strategy to boost tumor immunity and organization of functional TLS to overcome limitations of ICB in HPV- HNSCC."

Biomarker • Clinical • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD21 • FCER2 • SEMA4D

Treatment with Pepinemab, Anti-SEMA4D Blocking Antibody, Reduces a Unique Astrocyte Subset (Ast10) Correlated with Cognitive Decline and Associated Biomarkers of Synaptic Loss in People with Early-Stage AD (CTAD 2026) - No abstract available

Biomarker • SEMA4D

VX15/2503 in Combination With Ipilimumab or Nivolumab in Patients With Head and Neck Cancer (clinicaltrials.gov) - P1 | N=35 | Active, not recruiting | Sponsor: Emory University | Recruiting ➔ Active, not recruiting | N=50 ➔ 35 | Trial primary completion date: Jun 2026 ➔ Apr 2027

Biomarker • Enrollment change • Enrollment closed • Trial primary completion date • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Vaccinex to Report New Biomarker Data and Plans for Phase 2B Clinical Trial of Pepinemab in AD at the Alzheimer’s Association International Conference in London on July 13, 2026 (The Manila Times) - "Elizabeth Evans, PhD, Chief Operating Officer and Senior VP Discovery and Translational Medicine, will chair the Featured Research Session and present novel results of the SIGNAL-AD phase 1/2 study and plans for continued investigation in the SIGNAL-AD2 study....Evidence from these studies support and inform the design of an enlarged randomized Phase 2B trial 'SIGNAL-AD2' for the treatment of people living with early Alzheimer's dementia."

New P2b trial • P1/2 data • Alzheimer's Disease • Dementia

Glial Biomarkers Associated With Disease Progression Are Regulated By SEMA4D Blocking Antibody Pepinemab In Patients With Early-stage AD (AAIC 2026) - No abstract available

Biomarker • Clinical • Alzheimer's Disease • CNS Disorders • SEMA4D

KEYNOTE B84: Pepinemab in Combination With Pembrolizumab in Advanced, Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (clinicaltrials.gov) - P1b/2; N=80; Recruiting; Sponsor: Vaccinex Inc.; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4 • MRI • PD-L1

KEYNOTE B84: Pepinemab in Combination With Pembrolizumab in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (clinicaltrials.gov) - P1/2 | N=65 | Recruiting | Sponsor: Vaccinex Inc. | Phase classification: P1b/2 ➔ P1/2 | Trial completion date: Sep 2023 ➔ Dec 2024 | Trial primary completion date: Sep 2023 ➔ Dec 2024

Combination therapy • Metastases • Phase classification • Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4 • IFNG • IL10 • IL2 • IL6 • PD-L1 • TGFB1 • TNFA

KEYNOTE B84: Pepinemab in Combination With Pembrolizumab in Advanced, Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck (clinicaltrials.gov) - P1b/2; N=80; Recruiting; Sponsor: Vaccinex Inc.; Initiation date: May 2021 ➔ Aug 2021

Clinical • Combination therapy • Trial initiation date • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD4 • MRI • PD-L1

Adoptive T Cell Therapy Following HER2-Pulsed Dendritic Cell Vaccine & Pepinemab /Trastuzumab in Patients w/ Metastatic HER2+ Breast Cancer (clinicaltrials.gov) - P1 | N=28 | Suspended | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Recruiting ➔ Suspended | Trial primary completion date: Apr 2026 ➔ Aug 2026

Trial primary completion date • Trial suspension • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PGR

A single-cell fixed RNA profiling uncovers key transcriptional and signalling programs in liver fibrosis progression and regression (EASL 2026) - "Recombinant SEMA4D induces type I collagen in HSCs, whereas humanised monoclonal IgG4 SEMA4D blockade (VX15/2503) attenuates fibrosis in vivo... This FLEX-based single-cell atlas revealed critical transcriptional programs and cell-cell interactions, identifying SEMA4D and LMCD1 as promising therapeutic targets for liver fibrosis."

Fibrosis • Hepatology • Immunology • Liver Cirrhosis • MMP14 • SEMA4D

Regulating dendritic cells to promote mature tertiary lymphoid structures and enhance anti-tumor immunity (AACR 2025) - P1, P1/2 | "KEYNOTE-B84 study (NCT04815720) evaluated the safety and efficacy of pepinemab in combination with pembrolizumab as a first-line treatment for immunotherapy-naïve patients with R/M HNSCC. Neoadjuvant studies in patients with surgically resectable metastatic melanoma (NCT03769155) and HNSCC (NCT03690986) received pepinemab treatment combined with nivolumab and/or ipilimumab...When combined with ICI, pepinemab induced de novo formation of TLS that correlated with clinical benefit, even in poorly immunogenic tumors that do not respond well to ICI, including HPV-negative and PD-L1 low HNSCC. When combined with modalities to further expand DC, SEMA4D blocking antibodies inhibited tumor growth in preclinical models, including in ICI-resistant models."

IO biomarker • Head and Neck Cancer • Melanoma • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CD8 • CXCR5 • FLT3 • PD-L1 • SEMA4D

Context-Dependent Dual Roles of the Plexin-B Family in Cancer Progression: Mechanisms and Therapeutic Implications. (PubMed, Cancer Manag Res) - "A central thesis of this review is that these six contextual determinants establish a framework for understanding receptor pleiotropy. Furthermore, while targeting Plexin-B signaling shows therapeutic promise (eg, pepinemab in clinical trials), indiscriminate inhibition risks abrogating tumor-suppressive functions and perturbing immune microenvironment homeostasis, underscoring the necessity for biomarker-driven stratification to prevent paradoxical oncogenic consequences."

Journal • Review • Brain Cancer • Breast Cancer • Genetic Disorders • Glioma • Melanoma • Oncology • Skin Cancer • Solid Tumor • Triple Negative Breast Cancer • PLXNB1 • RHOA

Defining the mechanism of semaphorin4D tumorigenesis in prostate cancer models (AACR 2025) - "Loss of SEMA4D function could disrupt vascularization, creating hypoxia that induces tumor cell apoptosis. Two mouse models—subcutaneous Myc-CaP allografts in immunocompetent mice and Hi-Myc prostate cancer GEMM were treated with a SEMA4D blocking mAb (pepinemab) to inhibit SEMA4D signaling... Our findings suggest that SEMA4D inhibition effectively arrests tumor growth by disrupting angiogenesis and potentially regulating immune activity, alongside inducing hypoxia and apoptosis. Ongoing transcriptomic analyses will further explore molecular mechanisms, including pathways involved in angiogenesis and immune regulation."

Preclinical • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • SEMA4D

Neoadjuvant pepinemab enhances DC function associated with mature tertiary lymphoid structures and activity of immune checkpoint blockade in patients with metastatic melanoma (AACR 2025) - P1 | "A neoadjuvant window of opportunity study was designed to evaluate activity and efficacy of pepinemab, SEMA4D blocking antibody, combined with nivolumab (nivo) and/or ipilimumab (ipi) in patients with surgically resectable metastatic melanoma. All patients receiving triple combination therapy (8/8) were recurrence-free at 24 months with mature TLS in the resected tumors (6/6). Pepinemab represents a novel strategy to boost dendritic cell infiltration, activation, and organization of functional TLS to overcome limitations of ICB."

Checkpoint block • Checkpoint inhibition • Clinical • IO biomarker • Metastases • Melanoma • Oncology • Solid Tumor • CD163 • CD4 • CDK1 • CXCR5 • FLT3 • SEMA4D

Single-cell fixed RNA profiling uncovers SEMA4D and LMCD1 as therapeutic targets in a liver fibrosis model. (PubMed, JHEP Rep) - "This FLEX-based single-cell atlas revealed critical transcriptional programs and cell-cell interactions, identifying SEMA4D and LMCD1 as promising therapeutic targets for liver fibrosis."

Journal • Fibrosis • Hepatocellular Cancer • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Solid Tumor • MMP14 • SEMA4D

Adoptive T Cell Therapy Following HER2-Pulsed Dendritic Cell Vaccine & Pepinemab /Trastuzumab in Patients w/ Metastatic HER2+ Breast Cancer (clinicaltrials.gov) - P1 | N=28 | Recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Dec 2025 ➔ Apr 2026

Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2 • PGR

Drug Development. (PubMed, Alzheimers Dement) - P1/2, P2 | "Given the many physiological parallels between glial activation and inflammatory processes in HD and AD, results from these studies suggest that preventing astrocyte activation and reducing brain inflammation and associated vascular disruption with pepinemab treatment could be an attractive alternative or complement to anti-Aβ antibodies and support the broad application of glial regulators to treat cognitive dysfunction and neurodegenerative disease."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Huntington's Disease • Inflammation • Movement Disorders • Multiple Sclerosis • FAP • GFAP • LILRB4 • PLXNB1 • SEMA4D

Vaccinex…announced that it has entered into a $60 million revenue sharing agreement with Pepinemab Development Venture, LP (PDV) to continue advancing development of its pepinemab anti-SEMA4D antibody in an enlarged phase 2b clinical trial for treatment of AD (GlobeNewswire) - "The agreements provide that, in exchange for the commitment of funding, PDV will receive 50% of future economic proceeds received by Vaccinex from a development partner or licensee of pepinemab related to neurological indications and 25% related to other indications. This agreement follows on promising data previously reported from studies in animal disease models and in the early stage SIGNAL-AD phase 1/2a clinical trial..."

Financing • Licensing / partnership • Alzheimer's Disease

Biomarkers Associated with Response to Treatment of Early Stage AD with Pepinemab, Anti-SEMA4D Blocking Antibody (CTAD 2025) - No abstract available

Biomarker • Alzheimer's Disease • CNS Disorders • SEMA4D

Neoadjuvant pepinemab enhances immune checkpoint blockade in metastatic melanoma characterized by biomarkers of TME reprogramming including tertiary lymphoid structures (SITC 2025) - P1 | "Pepinemab, a novel semaphorin 4D (Sema4D) blocking antibody, reprograms myeloid-driven immune suppression and activates dendritic cells within the tumor microenvironment (TME), offering a complementary mechanism to enhance ICI efficacy.1 2Methods The phase II integrated biomarker clinical trial (NCT03769155) evaluated neoadjuvant pepinemab in combination with nivolumab and/or ipilimumab in patients with resectable metastatic melanoma. Mature (mTLS) defined as CD21+/- CD23+ CD20+ aggregates. Squares denote an event (recurrence or death)"

Biomarker • Checkpoint block • Checkpoint inhibition • Clinical • IO biomarker • Metastases • Melanoma • Oncology • Solid Tumor • CD20 • CD21 • CD4 • CD8 • FCER2 • SEMA4D

Neoadjuvant pepinemab enhances immune checkpoint blockade in metastatic melanoma characterized by biomarkers of TME reprogramming including tertiary lymphoid structures (SITC 2025) - P1 | "Pepinemab, a novel semaphorin 4D (Sema4D) blocking antibody, reprograms myeloid-driven immune suppression and activates dendritic cells within the tumor microenvironment (TME), offering a complementary mechanism to enhance ICI efficacy.1 2Methods The phase II integrated biomarker clinical trial (NCT03769155) evaluated neoadjuvant pepinemab in combination with nivolumab and/or ipilimumab in patients with resectable metastatic melanoma. Mature (mTLS) defined as CD21+/- CD23+ CD20+ aggregates. Squares denote an event (recurrence or death)"

Biomarker • Checkpoint block • Checkpoint inhibition • Clinical • IO biomarker • Metastases • Melanoma • Oncology • Solid Tumor • CD20 • CD21 • CD4 • CD8 • FCER2 • SEMA4D

VX15/2503 in Combination With Ipilimumab or Nivolumab in Patients With Head and Neck Cancer (clinicaltrials.gov) - P1 | N=50 | Recruiting | Sponsor: Emory University | Trial completion date: Nov 2025 ➔ Nov 2027 | Trial primary completion date: Jun 2025 ➔ Jun 2026

Biomarker • Trial completion date • Trial primary completion date • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Regulation of Vascular Calcification by M1-Type Macrophage-Derived Semaphorin 4D. (PubMed, Int J Mol Sci) - "Notably, neutralization of Sema4D in M1 conditioned medium using pepinemab, an anti-Sema4D antibody, effectively attenuated VSMC calcification induced by M1 macrophages. Conversely, supplementation of conditioned medium with recombinant Sema4D enhanced calcification and osteogenic signaling in VSMCs, further supporting the pro-calcifying role of Sema4D. Collectively, these findings highlight macrophage-derived Sema4D as a pivotal regulator of vascular calcification and a promising therapeutic target."

Journal • Atherosclerosis • Cardiovascular • SEMA4D

Vaccinex to Report Promising New Clinical Results of Neoadjuvant Treatment with Pepinemab to Enhance Immunotherapy in Patients with Head and Neck Cancer at ASCO Annual Meeting (GlobeNewswire) - P1 | N=50 | NCT03690986 | "Pepinemab has potential to be a major advance for HNSCC patients with cold and resistant disease, with capacity of a well-tolerated and effective treatment that can induce formation and harness the power of TLS to optimize the clinical benefit of immunotherapy. Our data demonstrate that the addition of pepinemab to neoadjuvant immune checkpoint treatments did not compound toxicities, yet it enhanced TLS maturity that correlated with improved pathologic response. Collectively, these results highlight the potential of pepinemab to turn immunologically cold tumors, such as HPV-negative head and neck cancer, into hot immune centers by inducing robust and mature TLS."

P1 data • Squamous Cell Carcinoma of Head and Neck