Immunotherapy with immunocytokines and PD-1 blockade enhances the anticancer activity of small molecule-drug conjugates targeting carbonic anhydrase IX
Autor: | Sheila Dakhel Plaza, Alessandra Villa, Emanuele Puca, Aureliano Zana, Christiane Krudewig, Samuele Cazzamalli, Dario Neri, Jacopo Millul |
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Přispěvatelé: | University of Zurich |
Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Cancer Research Colorectal cancer medicine.medical_treatment Cell Mice Nude 10184 Institute of Veterinary Pathology Antineoplastic Agents Mice 03 medical and health sciences 0302 clinical medicine Renal cell carcinoma medicine Animals Humans Cytotoxic T cell Carbonic Anhydrase IX Immune Checkpoint Inhibitors 030304 developmental biology 0303 health sciences Kidney business.industry Immunotherapy medicine.disease Fusion protein Small molecule 3. Good health Blockade 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research 570 Life sciences biology Female business |
Popis: | Small molecule-drug conjugates (SMDCs) represent an alternative to conventional antitumor 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 describe 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 antibody-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 domain of fibronectin containing the murine interleukin-12 moiety, was active also against large established tumors. Analysis of the microscopic structures of healthy organs performed three months after tumor eradication confirmed absence of pathological abnormalities 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 carcinoma and of hypoxic tumors. |
Databáze: | OpenAIRE |
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