Immune Suppression Enhances Effectiveness of Mesothelioma Targeted Immunotoxin

Major tumor response in a patient with pleural mesothelioma who had progressive disease while enrolled in the protocol. Red asterisk show mesothelioma involving the right pleura

Major tumor response in a patient with pleural mesothelioma who had progressive disease while enrolled in the protocol. Red asterisks show mesothelioma involving the right pleura.

Malignant mesothelioma is an aggressive cancer of the linings of the organs in the chest and the abdomen and is often caused by exposure to asbestos. Although patients with localized disease may be treated effectively with surgery, those with more-advanced mesothelioma have few approved treatment options.

To address the needs of these patients, researchers have begun to develop therapies targeted against mesothelin, a protein highly expressed on mesothelioma cells but absent from most normal cell types. Along this line, Ira Pastan, M.D., and Raffit Hassan, M.D., of CCR’s Laboratory of Molecular Biology, and their colleagues generated the anti-mesothelin immunotoxin, SS1P. The fusion of a portion of Pseudomonas exotoxin A and the variable region of a mesothelin-directed antibody, SS1P binds to and kills mesothelin-expressing cells by inhibiting protein synthesis and inducing apoptosis. In early clinical trials, SS1P was safe but elicited only minor antitumor activity as nearly all patients developed SS1P-neutralizing antibodies after a single cycle of treatment.

Since development of human antibody response to immunotoxins limits their efficacy, Pastan, Hassan, Daniel Fowler, M.D., of CCR’s Experimental Transplantation and Immunology Branch, and their colleagues wondered whether depleting B and T lymphocytes might reduce the immune response to SS1P. The researchers showed in mice that a combination of pentostatin and cyclophosphamide with SS1P reduced the formation of anti-SS1P antibodies.

To test the pentostatin/cyclophosphamide/SS1P combination in humans, Hassan recruited 11 patients, nine with pleural mesothelioma and two with peritoneal mesothelioma. All patients had advanced bulky disease that had failed standard treatment options and had progressive disease at enrollment. Out of the 10 evaluable patients treated, three had objective tumor response, including two with complete metabolic response by positron emission tomography (PET). The three patients with objective partial response by computed tomography (CT) imaging had between 44 and 74 percent shrinkage of their tumors, and all of them are alive more than 15 months from enrollment. In addition, two patients who initially did not respond to SS1P had major tumor responses to subsequent chemotherapy to which they had not responded previously. Such major and durable tumor responses are unprecedented in patients with treatment refractory mesothelioma whose average expected overall survival is 4-6 months.

The regimen of pentostatin/cyclophosphamide/SS1P was well tolerated. Using a standard safety grading scale of 1 to 4, the researchers observed no grade 4 toxicities due to SS1P. However, some patients experienced grade 3 chest, back, or pleuritic pain (9 percent each). In response to pentostatin and cyclophosphamide, all patients had grade 4 lymphocyte reduction, while 9 percent of patients, each, experienced grade 3 anemia or fever and 18 percent had grade 3 elevated liver enzymes. No patients acquired viral, bacterial, or fungal infections.

Finally, the investigators showed that the addition of pentostatin and cyclophosphamide delayed SS1P-neutralizing antibody formation. The majority of patients were able to receive more than one cycle of SS1P, and one patient had no detectible antibodies after six cycles of treatment. The researchers also found that, in general, high SS1P levels in patient serum correlated with the delay in antibody formation and that SS1P serum levels were 100 times higher than the established in vitro cytotoxic concentration.

Taken together, Hassan, Pastan, and colleagues showed that adding pentostatin and cyclophosphamide to SS1P was safe and led to dramatic tumor responses in heavily pretreated patients with mesothelioma. While the mechanism of this improved effect and the predictors of patient response are not yet clear, these results suggest that the combination may be useful for cancers beyond mesothelioma, such as pancreatic, lung, and ovarian cancers, that also express mesothelin.

Summary Posted: 11/2013

Reference

Hassan R, Miller AC, Sharon E, Thomas A, Reynolds JC, Ling A, Kreitman RJ, Miettinen MM, Steinberg SM, Fowler DH, Pastan I. Major Cancer Regressions in Mesothelioma After Treatment with an Anti-Mesothelin Immunotoxin and Immune Suppression. October 23, 2013 PubMed Link