Trastuzumab emtansine (T-DM1) renders HER2 ⁺ breast cancer highly susceptible to CTLA-4/PD-1 blockade

TLDR

Antibody‑drug conjugates such as T‑DM1 provide a powerful targeted therapy for HER2‑positive breast cancer. The study investigates how T‑DM1’s antitumor activity can be potentiated by combining it with CTLA‑4/PD‑1 blockade. T‑DM1 alone elicits strong antitumor immunity, and when paired with CTLA‑4/PD‑1 inhibition it cures HER2‑positive tumors by inducing massive T‑cell infiltration, TH1 polarization, and a regulatory T‑cell response that protects against inflammation.

Abstract

Targeted drug delivery with antibody-drug conjugates such as the HER2-directed ado-trastuzumab emtansine (T-DM1) has emerged as a powerful strategy for cancer therapy. We show that T-DM1 is particularly effective in eliciting antitumor immunity in patients with early breast cancer (WSG-ADAPT trial) and in a HER2-expressing orthotopic tumor model. In the latter, despite primary resistance to immunotherapy, combined treatment with T-DM1 and anti-CTLA-4/PD-1 (cytotoxic T lymphocyte-associated protein-4/programmed cell death protein-1) was curative because it triggered innate and adaptive immunity. Tumor rejection was accompanied by massive T cell infiltration, TH1 (T helper 1) cell polarization, and, notably, a substantial increase in regulatory T cells. Depletion of regulatory T cells resulted in inflammation and tissue damage, implying their essential role in protecting the host during therapy. This study provides insights into the mechanisms of T-DM1's therapeutic activity and a rationale for potential therapeutic combination strategies with immunotherapy.