A magic bullet for solid tumors: determining the therapeutic potential of anti-Mesothelin immunotoxins

Abstract

Immunotoxins are targeted cancer therapies consisting of a potent bacteria- or plant-derived toxin fused to a targeting moiety. They allow selective targeting and killing of cancer cells with minimal off-target effects. Immunotoxins have demonstrated success against hematological malignancies. However, there are significant barriers to their use against solid tumors. A critical factor in the effectiveness of immunotoxins is the identification of suitable target antigens. Mesothelin (MSLN) is a cell-surface glycoprotein of unknown function that is normally expressed in non-essential tissues but is overexpressed in a wide range of cancers, particularly in mesothelioma, pancreatic, ovarian cancer. Consequently, MSLN has been a focus of efforts to design effective immunotoxins against solid tumors. Despite these promising factors, no breakthroughs have been achieved. Two generations of genetically engineered Pseudomonas exotoxin A (PE)-based anti-MSLN RITs have been developed, but faced difficulties due to their high immunogenicity, toxicity and minor effects as single agents. Subsequently, combination treatment strategies led to enhanced activity in trials but often exacerbated toxicities. Given the poor prognosis and lack of treatment options for many MSLN-expressing tumors, identifying methods to overcome these challenges are urgently needed. This review examines recent advancements in the engineering of recombinant immunotoxins (RITs) which suggest a need reevaluate the potential of this approach as a viable intervention for solid tumors. The findings indicate that modular RITs can be designed with optimized properties to achieve efficient targeting and cytotoxicity, as well as reduced immunogenicity. Additionally, an emerging role for immunotoxins in antitumor immune activation mediated by their cell killing mechanism suggests a broader therapeutic utility for immunotoxins and a potential route for production of a new generation of highly effective targeted solid tumor therapies. To advance the development of anti-MSLN RITs, this study calls for incorporating fully deimmunized toxins with a novel targeting approach to tackle the problem of MSLN shedding and achieve effective cell killing to induce long-lasting antitumor immunity. Leveraging the unique features of immunotoxin design and activity can have a significant impact for some of the hardest-to-treat cancers.