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Brentuximab Vedotin-Driven Microtubule Disruption Results in Endoplasmic Reticulum Stress Leading to Immunogenic Cell Death and Antitumor Immunity.
Heiser, Ryan A; Cao, Anthony T; Zeng, Weiping; Ulrich, Michelle; Younan, Patrick; Anderson, Martha E; Trueblood, Esther S; Jonas, Mechthild; Thurman, Robert; Law, Che-Leung; Gardai, Shyra J.
Affiliation
  • Heiser RA; Seagen Inc., Bothell, Washington.
  • Cao AT; Seagen Inc., Bothell, Washington.
  • Zeng W; Seagen Inc., Bothell, Washington.
  • Ulrich M; Seagen Inc., Bothell, Washington.
  • Younan P; Seagen Inc., Bothell, Washington.
  • Anderson ME; Seagen Inc., Bothell, Washington.
  • Trueblood ES; Seagen Inc., Bothell, Washington.
  • Jonas M; Seagen Inc., Bothell, Washington.
  • Thurman R; Seagen Inc., Bothell, Washington.
  • Law CL; Seagen Inc., Bothell, Washington.
  • Gardai SJ; Seagen Inc., Bothell, Washington.
Mol Cancer Ther ; 23(1): 68-83, 2024 Jan 03.
Article in En | MEDLINE | ID: mdl-37775098
ABSTRACT
Brentuximab vedotin, a CD30-directed antibody-drug conjugate (ADC), is approved for clinical use in multiple CD30-expressing lymphomas. The cytotoxic payload component of brentuximab vedotin is monomethyl auristatin E (MMAE), a highly potent microtubule-disrupting agent. Preclinical results provided here demonstrate that treatment of cancer cells with brentuximab vedotin or free MMAE leads to a catastrophic disruption of the microtubule network eliciting a robust endoplasmic reticulum (ER) stress response that culminates in the induction of the classic hallmarks of immunogenic cell death (ICD). In accordance with the induction of ICD, brentuximab vedotin-killed lymphoma cells drove innate immune cell activation in vitro and in vivo. In the "gold-standard" test of ICD, vaccination of mice with brentuximab vedotin or free MMAE-killed tumor cells protected animals from tumor rechallenge; in addition, T cells transferred from previously vaccinated animals slowed tumor growth in immunodeficient mice. Immunity acquired from killed tumor cell vaccination was further amplified by the addition of PD-1 blockade. In a humanized model of CD30+ B-cell tumors, treatment with brentuximab vedotin drove the expansion and recruitment of autologous Epstein-Barr virus-reactive CD8+ T cells potentiating the activity of anti-PD-1 therapy. Together, these data support the ability of brentuximab vedotin and MMAE to drive ICD in tumor cells resulting in the activation of antigen-presenting cells and augmented T-cell immunity. These data provide a strong rationale for the clinical combination of brentuximab vedotin and other MMAE-based ADCs with checkpoint inhibitors.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Immunoconjugates / Epstein-Barr Virus Infections Limits: Animals Language: En Journal: Mol Cancer Ther Year: 2024 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Immunoconjugates / Epstein-Barr Virus Infections Limits: Animals Language: En Journal: Mol Cancer Ther Year: 2024 Document type: Article