Major Cancer Regressions in Mesothelioma After Treatment with an Anti-Mesothelin Immunotoxin and Immune Suppression

In patients with advanced chemotherapy-refractory mesothelioma, treatment with the anti-mesothelin immunotoxin SS1P and immunosuppression with pentostatin and cyclophosphamide resulted in marked and durable tumor regressions. Combating Mesothelioma by Suppressing Friendly Fire Immunotoxins, which combine a bacterial toxin with an antibody fragment that recognizes a specific protein, offer a way to selectively target and kill cancer cells. Unfortunately, the patient’s immune system usually attacks the immunotoxin as a foreign protein, destroying it before it can reach its target and deliver the toxin to the tumor. Now, Hassan and coauthors have demonstrated a combination treatment approach for preventing the formation of antitoxin antibodies in mesothelioma patients. Mesothelioma is an aggressive tumor of the pleural and peritoneal membranes, which normally has a poor prognosis and very limited treatment options. SS1P is an immunotoxin targeting mesothelin, a protein that is only found in the mesothelial membranes and highly expressed in mesothelioma. In past clinical trials, the vast majority of treated patients developed antibodies against SS1P after only one cycle of treatment, precluding its continued use as a therapeutic agent. To overcome this problem, Hassan et al. treated chemotherapy-resistant mesothelioma patients with pentostatin and cyclophosphamide, chemotherapeutic agents that specifically deplete lymphocytes and can therefore prevent the formation of antitoxin antibodies, before giving SS1P to the patients. This treatment combination greatly delayed antibody formation, allowing the patients to receive multiple cycles of SS1P, which resulted in improved clinical outcomes. Future work will be needed to further prolong the presence of this immunotoxin because most patients in the current trial eventually developed antibodies against SS1P. Additional work will also be necessary to clarify the mechanism of the combination treatment and determine whether the immunomodulatory drugs contribute any direct antitumor effects. Nevertheless, the results presented by Hassan and coauthors provide a promising approach for treating an aggressive and deadly tumor, and demonstrate a clever way to overcome immune rejection of immunotoxin treatment. Immunotoxins are potent anticancer agents with an unusual mechanism of action: inhibition of protein synthesis resulting in apoptotic cell death. Immunotoxins have produced many durable complete responses in refractory hairy cell leukemia, where patients rarely form antibodies to the bacterial toxin component of the immunotoxin. Patients with mesothelioma, however, have normal immune systems and form antibodies after one cycle, and tumor responses to the immunotoxin have not been observed in this disease. We describe the results of a trial in which major antitumor responses were seen in patients with advanced mesothelioma who received the anti-mesothelin immunotoxin SS1P, together with pentostatin and cyclophosphamide, to deplete T and B cells. Of 10 patients with chemotherapy-refractory mesothelioma, 3 have had major tumor regressions with 2 ongoing at 15 months, and 2 others responded to chemotherapy after discontinuing immunotoxin therapy. Antibody formation was markedly delayed, allowing more SS1P cycles to be given, but this alone does not appear to account for the marked antitumor activity observed.