Tumor immunotherapy: drug-induced neoantigens (xenogenization) and immune checkpoint inhibitors
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Ornella Franzese1, Francesco Torino2, Maria Pia Fuggetta3, Angelo Aquino1, Mario Roselli2, Enzo Bonmassar1,3, Anna Giuliani3 and Stefania D’Atri4
1 Department of Systems Medicine, School of Medicine, University of Rome Tor Vergata, Rome, Italy
2 Department of Systems Medicine, Medical Oncology, University of Rome Tor Vergata, Rome, Italy
3 Institute of Translational Pharmacology, National Council of Research, Rome, Italy
4 Laboratory of Molecular Oncology, Istituto Dermopatico dell’Immacolata-IRCCS, Rome, Italy
Stefania D’Atri, email:
Enzo Bonmassar, email:
Keywords: triazene compounds, DNA repair, drug-induced neoantigens, immune checkpoints, cancer immunotherapy
Received: November 09, 2016 Accepted: January 24, 2017 Published: March 17, 2017
More than 40 years ago, we discovered that novel transplantation antigens can be induced in vivo or in vitro by treating murine leukemia with dacarbazine. Years later, this phenomenon that we called “Chemical Xenogenization” (CX) and more recently, “Drug-Induced Xenogenization” (DIX), was reproduced by Thierry Boon with a mutagenic/carcinogenic compound (i.e. N-methyl-N’-nitro-N-nitrosoguanidine). In both cases, the molecular bases of DIX rely on mutagenesis induced by methyl adducts to oxygen-6 of DNA guanine. In the present review we illustrate the main DIX-related immune-pharmacodynamic properties of triazene compounds of clinical use (i.e. dacarbazine and temozolomide).
In recent years, tumor immunotherapy has come back to the stage with the discovery of immune checkpoint inhibitors (ICpI) that show an extraordinary immune-enhancing activity. Here we illustrate the salient biochemical features of some of the most interesting ICpI and the up-to-day status of their clinical use. Moreover, we illustrate the literature showing the direct relationship between somatic mutation burden and susceptibility of cancer cells to host’s immune responses.
When DIX was discovered, we were not able to satisfactorily exploit the possible presence of triazene-induced neoantigens in malignant cells since no device was available to adequately enhance host’s immune responses in clinical settings. Today, ICpI show unprecedented efficacy in terms of survival times, especially when elevated mutation load is associated with cancer cells. Therefore, in the future, mutation-dependent neoantigens obtained by appropriate pharmacological intervention appear to disclose a novel approach for enhancing the therapeutic efficacy of ICpI in cancer patients.
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