NIH Research Festival
Introduction: Antibodies to cytotoxic T-lymphocyte-associated protein 4 (CTLA4) potentiate an immune response against cancer. RG7787 is a recombinant immunotoxin composed of an anti-mesothelin Fab fused to a fragment of Pseudomonas exotoxin A (PE). RG7787 is currently tested in phase 1. We previously observed that an anti-mesothelin immunotoxin produced major tumor regressions in humans when combined with Cytoxan and Pentostatin apparently due to T cell activation. We hypothesize that combining RG7787 with anti CTLA4 will promote cancer elimination. Methods: We transfected the 66C14 mouse breast cancer cell line with human mesothelin and grew the cancer cells in BALB/c mice that express a human mesothelin transgene so that they will not reject the tumors. Anti-tumor activity was evaluated by intra tumoral-injection of RG7787 combined with intra-peritoneal injection of anti CTLA4. Results: We found that combining RG7787 with anti CTLA4 produced a 76% complete remission (CR) rate, while CR was reached in only 15% of the mice under anti CTLA4 monotherapy. The survival benefit was statistically significantly (P= 0.0012). No mice reached CR after treatment with RG7787 alone or in the PBS treated controls. Furthermore, re-challenging of the mice with the parental cell line (66C14 without HuMsln) resulted in complete rejection of the tumor in all the mice. We also found treatment with antibodies to CD8 decreased the CR rate to 12%, indicating that CD8+ T cells are necessary for the response. Conclusions: Combining RG7787 with anti CTLA4 produces a high rate of complete remissions in a breast cancer model.
Scientific Focus Area: Immunology
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