Antimesothelin Immunotoxin Shows Potential for Malignant Pleural Mesothelioma
Mesothelin-targeted immunotoxin therapy is well tolerated by patients undergoing pemetrexed-cisplatin chemotherapy for malignant pleural mesothelioma
- Date: 04 Jul 2014
- Author: Lynda Williams, Senior medwireNews Reporter
- Topic: Drug Development / Cancer Immunology and Immunotherapy / Mesothelioma
medwireNews: An antimesothelin immunotoxin therapy can be used in combination with chemotherapy for first-line treatment of patients with advanced malignant pleural mesothelioma (MPM), early trial results suggest.
The phase I study found that SS1P - a recombinant variable Antibody fragment linked to PE38, a truncated portion of the Pseudomonas exotoxin - was well tolerated when given to patients alongside pemetrexed and cisplatin and showed some suggestion of efficacy.
As reported in Cancer, 24 patients with unresectable stage III or IV chemotherapy-naive MPM in the trial were treated with at least one intravenous dose of SS1P of between 25 and 55 µg/kg, and 23 of the patients received at least one cycle of chemotherapy.
All patients experienced at least one adverse event but just one patient experienced dose-limiting toxicity - in the form of grade 3 fatigue - at an SSP1 dose of 55 µg/kg. Other grade 3 toxicities included hypoalbuminaemia, hypotension, oedema, back pain and weight gain.
The maximum tolerated dose was therefore set at 45 µg/kg, report Raffit Hassan and co-authors, from the National Cancer Institute in Bethesda, Maryland, USA.
Of the 20 evaluable patients, radiological assessment revealed that 60% achieved a partial response, 15% had stable disease and 20% had progressive disease; for the 10 patients given the maximum tolerated dose, these rates were 77%, 8% and 15%, respectively.
Although baseline serum levels of mesothelin, CA 125 and megakaryocyte potentiating factor (MPF) did not predict SS1P/chemotherapy response, there was a significant correlation between changes in the biomarkers and a partial response versus stable or progressive disease.
There was also a significant difference in the relative change of mesothelin and of MPF between patients with a partial response, stable disease and disease progression.
However, all but two of 21 assessed patients developed neutralising antibodies against SS1P after the first cycle of treatment and only these two patients achieved a maximum serum SS1P concentration above 150 ng/mL in the second cycle.
“Although the objective response rate appears to be higher than that reported in historical controls who received chemotherapy alone, the rapid development of antibodies likely hampered the efficacy of SS1P”, Hassan et al caution.
They therefore conclude: “Strategies being explored to minimize immunogenicity and allow for repeated therapeutic administration of SS1P include modification of the immunotoxin protein structure to decrease its immunogenicity and/or host immune depletion”.
Hassan R, Sharon E, Thomas A, et al. Phase 1 study of the antimesothelin immunotoxin SS1P in combination with pemetrexed and cisplatin for front-line therapy of pleural mesothelioma and correlation of tumor response with serum mesothelin, megakaryocyte potentiating factor, and cancer antigen 125. Cancer 2014; First published online 2 July. DOI: 10.1002/cncr.28875
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