Immunotherapy with immunocytokines and PD-1 blockade enhances the anticancer activity of small molecule-drug conjugates targeting carbonic anhydrase IX

Small molecule-drug conjugates (SMDCs) represent an alternative to conventional anti-tumor chemotherapeutic agents, with the potential to improve the therapeutic window of cytotoxic payloads through active delivery at the site of the disease. In this article we de-scribe novel combination therapies consisting of anti-Carbonic Anhydrase IX SMDCs combined with different immunomodulatory products. The therapeutic effect of the SMDCs was potentiated by combination with PD-1 blockade and with tumor-homing anti-body-cytokine fusions in mouse models of renal cell carcinoma and colorectal cancer. The combination with L19-IL12, a fusion protein specific to the alternatively-spliced EDB do-main of fibronectin containing the murine interleukin-12 moiety, was active also against large established tumors. Analysis of the microscopic structures of healthy organs per-formed three months after tumor eradication confirmed absence of pathological abnormali-ties in the healthy kidney, liver, lung, stomach and intestine. Our findings may be of clinical significance as they provide motivation for the development of combinations based on small molecule-drug conjugates and immunotherapy for the treatment of renal cell carcino-ma and of hypoxic tumors.