Ultrasound-guided intra-tumor injection of combined immunotherapy cures mice from orthotopic prostate cancer
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Original Article
Ultrasound‑guided intra‑tumor injection of combined immunotherapy cures mice from orthotopic prostate cancer Giorgio Mauri · Claudia Chiodoni · Mariella Parenza · Ivano Arioli · Claudio Tripodo · Mario Paolo Colombo
Received: 27 March 2013 / Accepted: 5 October 2013 / Published online: 18 October 2013 © Springer-Verlag Berlin Heidelberg 2013
Abstract Intra-tumor injection of immunotherapeutic agents is often the most effective, likely because of concomitant modification of tumor microenvironment. We tested an immunotherapeutic regimen consisting of CpG oligonucleotides and of adenovirus-mediated gene delivery of CCL16 chemokine directly into orthotopically implanted prostate tumors by ultrasound-guided injection, followed by systemic administration of an anti-IL-10R antibody. This combination treatment induced rapid stromal rearrangement, characterized by massive leukocyte infiltration and large areas of necrosis, a scenario that eventually led to complete tumor rejection and systemic immunity in 75 % of the treated mice. In vivo T lymphocyte depletion experiments demonstrated that the efficacy of CCL16/CpG/ anti-IL-10R combination treatment relies upon CD8 T lymphocytes whereas CD4 T cells are dispensable. The results underlie the feasibility of echo-guided local immunotherapy of tumors located in visceral organs that are not easily accessible. Keywords Local cancer immunotherapy · Ultrasoundguided immunotherapy · Combination treatment · CpG oligonucleotides · CCL-16 · Prostate tumor
G. Mauri · C. Chiodoni · M. Parenza · I. Arioli · M. P. Colombo (*) Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Via Amadeo 42, 20133 Milan, Italy e-mail: [email protected] C. Tripodo Department of Human Pathology, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy
Introduction The failure of most immunotherapeutic approaches against established tumors is mainly due to unfavorable local environment dominated by immunosuppression [1]. The local delivery of cytokines can change the number and the phenotype of infiltrating immune cells, but when given as single agents, they generally fail to change tumor outcome [2]. However, the combination of vaccines, cytokines or chemokines with CpG oligonucleotides or other Toll-like receptor agonists is quite effective in several experimental models and could find clinical application [3]. Chemokines delivered as coding cDNAs ensure substantial local production, and adenoviral vectors are the most used because of transduction efficacy and transient, but elevated, transgene expression [4–6]. This approach that requires tumor accessibility for local injection has not been effectively tested in case of deep/visceral tumors being most preclinical works done by using subcutaneously implanted tumors [7]. To mimic visceral growing tumors, we established a new tumor cell line from an ex vivo transgenic adenocarcinoma of the mouse prostate (TRAMP) that is able to grow b
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