Abstract
Background: The immunotoxin 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 and unlike other anti-cancer drugs, SS1P does not suppress the immune system. Here we determined if SS1P can cooperate with anti-CTLA-4 to induce anti-tumor immunity and cause tumor regression.
Methods: 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. Twelve days after treatment initiation, the tumors were harvested and evaluated for immune related gene expression by Nanostring Technologies. A portion of each tumor was sent to pathology and stained for CD8.
Results: In mice treated with anti-CTLA-4 and SS1P, complete tumor regressions occurred in 25/30 (86%) SS1P injected tumors and in 16/30 (53%) tumors at the un-injected location. No complete regressions occurred with either drug given separately. This indicates that the combination therapy has a synergistic and systemic anti-tumor effect. Pathological evaluation of injected tumors from combination-treated mice revealed large central abscesses surrounded by a collar of inflammation, containing a mixture of lymphocytes and mononuclear cells. The collar of inflammation was unique to the combination treated mice. Only very small abscesses were observed in tumors from control mice. Immunohistochemistry of tumors from mice treated with SS1P and anti-CTLA-4 showed an increase in CD8+ cells located mainly in the inflammation collar. Analysis of gene expression in tumors from combination-treated mice, compared to PBS-treated tumors, showed that 341/747 (45%) immune transcripts were elevated by 2-fold or more including CD8a, PDL2 and CD56 (8, 15 and 24-fold, respectively). In mice treated with anti-CTLA-4 and PBS, the increase of transcripts was lower: 127/747 (17%) genes. Only 18 out of 747 transcripts (2%) were elevated in the SS1P-treated tumors. This suggests that SS1P by itself does not initiate an inflammatory process. However, SS1P greatly potentiates the inflammatory process initiated by anti-CTLA-4.
Conclusions: Combining local SS1P with anti-CTLA-4 promotes massive inflammation that cures injected and un-injected tumors and provides a strong rational to explore this combination therapy in patients.
Citation Format: Yasmin Leshem, James O'Brien, Yoram Reiter, Ira Pastan. Synergy between intratumoral immunotoxin and systemic anti-CTLA-4 promotes massive inflammation and leads to complete regression of tumors in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1767.
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