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An Antibody-Drug Conjugate Directed to Tissue Factor Shows Preclinical Antitumor Activity in Head and Neck Cancer as a Single Agent and in Combination with Chemoradiotherapy.
Bakema, Jantine E; Stigter-van Walsum, Marijke; Harris, Jeffrey R; Ganzevles, Sonja H; Muthuswamy, Anantharaman; Houtkamp, Mischa; Plantinga, Theo S; Bloemena, Elisabeth; Brakenhoff, Ruud H; Breij, Esther C W; van de Ven, Rieneke.
Afiliação
  • Bakema JE; Department of Otolaryngology | Head & Neck Surgery, Amsterdam UMC, location VU University Medical Center, Amsterdam, The Netherlands.
  • Stigter-van Walsum M; Genmab, Utrecht, The Netherlands.
  • Harris JR; Department of Otolaryngology | Head & Neck Surgery, Amsterdam UMC, location VU University Medical Center, Amsterdam, The Netherlands.
  • Ganzevles SH; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands.
  • Muthuswamy A; Genmab US Inc., Plainsboro, New Jersey.
  • Houtkamp M; Department of Otolaryngology | Head & Neck Surgery, Amsterdam UMC, location VU University Medical Center, Amsterdam, The Netherlands.
  • Plantinga TS; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands.
  • Bloemena E; Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands.
  • Brakenhoff RH; Genmab US Inc., Plainsboro, New Jersey.
  • Breij ECW; Genmab, Utrecht, The Netherlands.
  • van de Ven R; Genmab, Utrecht, The Netherlands.
Mol Cancer Ther ; 23(2): 187-198, 2024 Feb 01.
Article em En | MEDLINE | ID: mdl-37828725
Head and neck squamous cell carcinoma (HNSCC) is a solid tumor type that arises in the squamous epithelial cells lining the mucosal surfaces of the upper aerodigestive tract. Long-term survival of patients with advanced disease stage remains disappointing with current treatment options. We show that tissue factor is abundantly expressed on patient-derived HNSCC cell lines, xenograft tumor material, and tumor biopsies from patients with HNSCC. Tisotumab vedotin (TV) is an antibody-drug conjugate (ADC) directed to tissue factor, a protein expressed in many solid tumors. HNSCC cells and xenograft tumors were efficiently eliminated in vitro and in vivo with TV-monotherapy compared with treatment with a control antibody conjugated to monomethyl auristatin E (MMAE). Antitumor activity of TV was also tested in vivo in combination with chemoradiotherapy, standard of care for patients with advanced stage HNSCC tumors outside the oral cavity. Preclinical studies showed that by adding TV to chemoradiotherapy, survival was markedly improved, and TV, not radiotherapy or chemotherapy, was the main driver of antitumor activity. Interestingly, TV-induced cell death in xenograft tumors showed an influx of macrophages indicative of a potential immune-mediated mode-of-action. In conclusion, on the basis of these preclinical data, TV may be a novel treatment modality for patients suffering from head and neck cancer and is hypothesized to improve efficacy of chemoradiotherapy. SIGNIFICANCE: This work shows preclinical in vitro and in vivo antitumor activity of the antibody-drug conjugate Tisotumab vedotin in head and neck cancer models, and enhanced activity in combination with chemoradiotherapy, supporting further clinical development for this cancer type.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Imunoconjugados / Neoplasias de Cabeça e Pescoço Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Imunoconjugados / Neoplasias de Cabeça e Pescoço Idioma: En Ano de publicação: 2024 Tipo de documento: Article