{
  "abstract": "Background Neoadjuvant immunotherapy is emerging as a critical component in the management of metastatic melanoma. While immune checkpoint inhibitors (ICIs) offer clinical benefit, resistance and disease recurrence remain major limitations, with a substantial proportion of patients failing to achieve pathologic and durable responses. 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 2 Methods The phase II integrated biomarker clinical trial ( NCT03769155) evaluated neoadjuvant pepinemab in combination with nivolumab and/or ipilimumab in patients with resectable metastatic melanoma. Patients received two preoperative doses, followed by curative-intent surgery and one year of adjuvant nivolumab. Primary study endpoints included multiomic profiling of surgical resected tumor tissue and peripheral blood to assess the immunologic effects of treatment, with a focus on TME modulation and T cell infiltration.Results Pathologic response was associated with TME remodeling, including neutralization of SEMA4D gradient, increased infiltration of CD4 + and CD8+ T cells, and the presence of intratumoral B cell aggregates, as demonstrated by multiplex immunohistochemistry (IHC) (figure 1). Bulk tumor transcriptional profiling revealed enrichment of B cell, T cell, and dendritic cell activation and antigen presentation gene signatures in responders. Peripheral and tumoral biomarkers of DC activation and recruitment were associated with pathologic response and improved recurrence free survival (RFS). Enrichment of non-canonical NF-κB and down-regulation of EMT and MAPK activation pathways were associated with clinical benefit.Pepinemab-containing regimens induced significantly more mature tertiary lymphoid structures (mTLS) within tumors, defined by multiplex IHC as organized B and T cell zones, CD21+ follicular dendritic cells, and CD23+ germinal centers (figure 2). mTLS were associated with both pathologic response and RFS. Patients receiving triple therapy exhibited the highest mTLS density, most pronounced immune activation, and greatest clinical benefit, including increased cytotoxic T cell clonal expansion and modulation of cytokine, chemokine, and B cell profiles.Conclusions Neoadjuvant pepinemab in combination with immune checkpoint blockade promotes robust TME remodeling, overcomes immune suppression, and enhances antitumor immunity through a distinct Sema4D-blocking mechanism. The regimen is safe, well tolerated, and demonstrates promising enhanced clinical activity in resectable metastatic melanoma.Trial Registration NCT03769155References Shafique MR, Fisher TL, Evans EE, et al. A phase Ib/II study of pepinemab in combination with avelumab in advanced non-small cell lung cancer. Clin Cancer Res. 2021;27(13):3630–3640. doi:10.1158/1078-0432.CCR-20-4792Clavijo PE, Friedman J, Robbins Y, et al. Semaphorin4D inhibition improves response to immune-checkpoint blockade via attenuation of MDSC recruitment and function. Cancer Immunol Res. 2019;7(2):282–291. doi:10.1158/2326-6066.CIR-18-0156Ethics Approval This study (Winship 4400-18; PI: Lowe) and its associated secondary use protocol (IRB-00009361; PI: Lesinski) were approved by the Emory University IRB. Written informed consent was obtained for all participants.Abstract 22 Figure 1TME remodeling. 1x and 20x magnification of representative images from non-pepinemab and pepinemab-containing post treatment surgical resectionsAbstract 22 Figure 2Pepinemab containing regimens promote formation of mature tertiary lymphoid structures linked to improved clinical outcomes. Immature (iTLS) defined as CD21- CD23- CD20+ aggregates. Mature (mTLS) defined as CD21+/- CD23+ CD20+ aggregates. Squares denote an event (recurrence or death)",
  "authors": [
    {
      "affiliations": [
        "Vaccinex, Inc, Rochester, NY, USA"
      ],
      "name": "Crystal L Mallow"
    },
    {
      "affiliations": [
        "Emory University, Decatur, GA, USA"
      ],
      "name": "Ayana T Ruffin"
    },
    {
      "affiliations": [
        "Emory University, Atlanta, GA, USA"
      ],
      "name": "Brian Olson"
    },
    {
      "affiliations": [
        "Emory University, Atlanta, GA, USA"
      ],
      "name": "Jacklyn Hammons"
    },
    {
      "affiliations": [
        "Winship Cancer Institute, Emory University, Atlanta, GA, USA"
      ],
      "name": "Shannon K Swisher"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Brenda Melendez"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Manoj Chelvanambi"
    },
    {
      "affiliations": [
        "Vaccinex, Inc, Rochester, NY, USA"
      ],
      "name": "Elaine M Gersz"
    },
    {
      "affiliations": [
        "Emory University School of Medicine, Atlanta, GA, USA"
      ],
      "name": "Megen C Wittling"
    },
    {
      "affiliations": [
        "Emory University School of Medicine, Atlanta, GA, USA"
      ],
      "name": "Laurence P Diggs"
    },
    {
      "affiliations": [
        "Emory University, Atlanta, GA, USA"
      ],
      "name": "Jayden Kim"
    },
    {
      "affiliations": [
        "Emory University, Atlanta, GA, USA"
      ],
      "name": "Brian Burns"
    },
    {
      "affiliations": [
        "Emory University, Atlanta, GA, USA"
      ],
      "name": "Agnes Harutyunyan"
    },
    {
      "affiliations": [
        "Vaccinex, Inc, Rochester, NY, USA"
      ],
      "name": "Christine Reilly"
    },
    {
      "affiliations": [
        "Vaccinex, Inc, Rochester, NY, USA"
      ],
      "name": "Terrence Fisher"
    },
    {
      "affiliations": [
        "Vaccinex, Inc, Rochester, NY, USA"
      ],
      "name": "Maurice Zauderer"
    },
    {
      "affiliations": [
        "Emory University School of Medicine, Atlanta, GA, USA"
      ],
      "name": "Keith A Delman"
    },
    {
      "affiliations": [
        "Emory University School of Medicine, Atlanta, GA, USA"
      ],
      "name": "Melinda Yushak"
    },
    {
      "affiliations": [
        "Emory University School of Medicine, Atlanta, GA, USA"
      ],
      "name": "Douglas Parker"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Jennifer A Wargo"
    },
    {
      "affiliations": [
        "Vaccinex, Inc, Rochester, NY, USA"
      ],
      "name": "Elizabeth E Evans"
    },
    {
      "affiliations": [
        "Winship Cancer Institute, Emory University, Atlanta, GA, USA"
      ],
      "name": "Chrystal M Paulos"
    },
    {
      "affiliations": [
        "Emory University School of Medicine, Atlanta, GA, USA"
      ],
      "name": "Michael C Lowe"
    },
    {
      "affiliations": [
        "Winship Cancer Institute, Emory University, Atlanta, GA, USA"
      ],
      "name": "Gregory B Lesinski"
    }
  ],
  "title": "22 Neoadjuvant pepinemab enhances immune checkpoint blockade in metastatic melanoma characterized by biomarkers of TME reprogramming including tertiary lymphoid structures",
  "uid": "86f4be4f-962d-5cd4-ab31-15061f4e71a1"
}