Synergistic Anti-tumor Activity of Local SS1P with Systemic CTLA-4 Blockade Causes Complete Regression of Both Injected and Un-injected Tumors in Mice

Abstract

Abstract SS1P consists of an anti-mesothelin Fv attached to Pseudomonas exotoxin A and kills tumor cells by inhibiting protein synthesis. Because of its unique mechanism of cell killing, SS1P does not inhibit the immune system like other anti-cancer drugs. Here we determined if SS1P can cooperate with anti-CTLA-4 to induce anti-tumor immunity and cause complete tumor regressions. A BALB/c breast cancer cell line was transfected with human mesothelin (66C14-M) and implanted in two different locations. SS1P was injected directly into one tumor and anti-CTLA-4 given IP. In mice treated with anti-CTLA-4 and SS1P, tumor regressions occurred in 11 out of 12 SS1P injected tumors (91%) and in 7 out of 12 un-injected tumors (53%). No tumor regressions occured with drugs given separately. Pathological evaluation showed a large sterile central abscess in injected tumors surrounded by a collar of inflammation containing a mixture of lymphocytes and other mononuclear cells. Analysis of responding tumors showed a time dependent increase in CD8+ cells located mainly in the inflammation collar. RNA analysis of responding tumors showed that 385/768 immune related gene transcripts were elevated by twofold or more including CD8a, PDL2 and IL1 alpha (13, 21 and 27-fold). Altogether, combining local SS1P with anti-CTLA-4 promotes massive inflammation that cures multi-centered cancer disease providing a strong rational to explore this combination therapy in patients.