Targeting MSLN-Positive Cancers: The Dual Role of MSLN-TTC in Immunogenic Cell Death and Immune Memory Induction

Mesothelin (MSLN)-targeted thorium conjugate (MSLN-TTC; BAY 2287411) represents a novel targeted alpha therapy under clinical investigation for MSLN-positive mesothelioma and ovarian cancer. This therapy combines anetumab, an antibody that targets MSLN, with a thorium-227 emitting alpha-particle used to induce DNA damage and cell death. Besides its direct cytotoxic effects, MSLN-TTC has been explored for its potential to stimulate immune responses, a characteristic shared with some forms of radiation therapy.

In vitro studies have shown that MSLN-TTC can upregulate markers indicative of immunogenic cell death in the human ovarian cancer cell line OVCAR-3, including calreticulin and HMGB-1. Additionally, MSLN-TTC prompts the secretion of pro-inflammatory cytokines such as IFN-β, IL-6, and IP-10. To assess in vivo efficacy, a syngeneic tumor model was utilized, necessitating the development of a MC38 cell line expressing human MSLN due to the lack of cross-reactivity with murine MSLN.

In this model, MSLN-TTC demonstrated a dose-dependent reduction in cell viability and induced significant antitumor activity following a single dose, with complete tumor eradication observed in a portion of the treated animals. Remarkably, animals that had been rendered tumor-free did not develop tumors upon re-challenge with the same cell line 121 days post-treatment, suggesting the induction of an immune memory response.

Collectively, these findings indicate that MSLN-TTC not only induces cell death but also has the capacity to stimulate an immune response in vitro and in vivo, offering a dual mechanism of action that could enhance the therapeutic potential for certain cancers.