Brentuximab Vedotin-Driven Microtubule Disruption Results in Endoplasmic Reticulum Stress Leading to Immunogenic Cell Death and Antitumor Immunity

• Published in: Molecular cancer therapeutics 2024-01, Vol.23 (1), p.68-83
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Biological Agents & Therapies; Brentuximab Vedotin; Cell Death And Senescence; Drug Mechanisms; Epstein-Barr Virus Infections; Herpesvirus 4, Human - metabolism; Immunoconjugates - therapeutic use; Immunogenic Cell Death; Ki-1 Antigen; Large Molecule Therapeutics; Mice; Microtubules - metabolism
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-23-0118

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.