Intratumoral injection of interferon‐α and systemic delivery of agonist anti‐CD137 monoclonal antibodies synergize for immunotherapy

• Published in: International journal of cancer 2011-01, Vol.128 (1), p.105-118
• Main Authors: Dubrot, Juan, Palazón, Asis, Alfaro, Carlos, Azpilikueta, Arantza, Ochoa, María Carmen, Rouzaut, Ana, Martinez‐Forero, Iván, Teijeira, Alvaro, Berraondo, Pedro, Le Bon, Agnes, Hervás‐Stubbs, Sandra, Melero, Ignacio
• Format: Article
• Language: English
• Subjects: 4‐1BB (CD137); Animal tumors. Experimental tumors; Animals; Antibodies, Monoclonal - administration & dosage; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Bone Marrow Cells - drug effects; Bone Marrow Cells - immunology; Bone Marrow Cells - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; combined immunotherapy; Drug Synergism; Experimental tumors, general aspects; Female; Flow Cytometry; Humans; immunostimulatory monoclonal antibodies; Immunotherapy; Immunotherapy - methods; Injections, Intralesional; Injections, Intraperitoneal; Interferon-alpha - administration & dosage; Lymph Nodes - drug effects; Lymph Nodes - immunology; Lymph Nodes - pathology; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms, Experimental - genetics; Neoplasms, Experimental - pathology; Neoplasms, Experimental - therapy; Pharmacology. Drug treatments; Receptor, Interferon alpha-beta - deficiency; Receptor, Interferon alpha-beta - genetics; Survival Analysis; Tumor Burden - drug effects; Tumor Necrosis Factor Receptor Superfamily, Member 9 - agonists; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology; Tumors; Type I interferon
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.25333

CD137 artificial costimulation results in complete tumor rejection in several mouse models. Type I interferons (IFN) exert antitumor effects through an array of molecular functions on malignant cells, tumor stroma and immune system cells. The fact that agonist anti‐CD137 mAb induce tumor regressions in mice deficient in the unique receptor for Type I IFNs (IFNAR−/−) indicated potential for treatment combinations. Indeed, combination of intratumor injections of mouse IFN‐α and intraperitoneal injections of anti‐CD137 mAb synergized as seen on subcutaneous lesions derived from the MC38 colon carcinoma, which is resistant to each treatment if given separately. Therapeutic activity was achieved both against lesions directly injected with IFN‐α and against distant concomitant tumors. Experiments in bone marrow chimeras prepared with IFNAR−/− and WT mice concluded that expression of the receptor for Type I interferons is mainly required on cells of the hematopoietic compartment. Synergistic effects correlated with a remarkable cellular hyperplasia of the tumor draining lymph nodes (TDLNs). Enlarged TDLNs contained more plasmacytoid and conventional dendritic cells (DC) that more readily cross‐presented. Importantly, numbers of both DC subtypes inversely correlated with the tumor size. Numbers of CD8 T cells specific for a dominant tumor antigen were increased at TDLNs by each separate treatment but only with slight augments due to the combination. Combined antitumor effects of the therapeutic strategy were also seen on subcutaneous TC‐1 tumors established for 24 days before treatment onset. The described strategy is realistic because (i) agents of each kind are clinically available and (ii) equivalent procedures in humans are feasible.