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 EBV-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.