Abstract
SS1P is an anti-mesothelin immunotoxin composed of a targeting antibody fragment genetically fused to a truncated fragment of Pseudomonas exotoxin A. Delayed responses reported in mesothelioma patients receiving SS1P suggest that anti-tumor immunity is induced. The goal of this study is to evaluate if SS1P therapy renders mesothelioma tumors more sensitive to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint blockade. We evaluated the ability of SS1P to induce adenosine triphosphate (ATP) secretion and calreticulin expression on the surface of AE17M mouse mesothelioma cells. Both properties are associated with immunogenic cell death. Furthermore, we treated these tumors with intra-tumoral SS1P and systemic CTLA-4. We found that SS1P increased the release of ATP from AE17M cells in a dose and time-dependent manner. In addition, SS1P induced calreticulin expression on the surface of AE17M cells. These results suggest that SS1P promotes immunogenic cell death and could sensitize tumors to anti-CTLA-4 based therapy. In mouse studies, we found that the combination of anti-CTLA-4 with intra-tumoral SS1P induced complete regressions in most mice and provided a statistically significant survival benefit compared to monotherapy. The surviving mice were protected from tumor re-challenge, indicating the development of anti-tumor immunity. These findings support the use of intra-tumoral SS1P in combination with anti-CTLA-4.
Highlights
The immune system can recognize cancer-associated antigens and eliminate some cancer cells [1,2].cancer cells that evolved into established tumors have outgrown or evaded the immune system
We found that anti-mesothelin immunotoxins increased the expression of surface calreticulin and the extracellular secretion of adenosine triphosphate (ATP)
SS1P is injected directly into AE17M tumors, it significantly enhances the effect of anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) therapy
Summary
The immune system can recognize cancer-associated antigens and eliminate some cancer cells [1,2]. The induction of markers of immunogenic cell death can predict the ability of drugs to induce anti-tumor immunity [8], and these types of drugs would be good candidates for the potential synergy with anti-CTLA-4. SS1P is the first generation of anti-mesothelin immunotoxins which has been tested in patients with mesothelin-expressing cancers. LMB-100 ( known as RG7787) is a second generation anti-mesothelin PE immunotoxin It contains a smaller fragment of PE (24 kDa) that is composed of enzymatically active domain III. Our previous work showed that injecting immunotoxins directly into tumors in combination with anti-CTLA-4 antibody had a synergistic anti-tumor effect in the 66C14 murine breast tumor model. We found that immunotoxin treatment promotes markers of immunogenic cell death in culture, and when injected directly into the tumors, immunotoxins enhance the effect of anti-CTLA-4 therapy
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
