In recent years, immune checkpoint inhibitors (ICpI) have provided the ground to bring tumor immunity back to life thanks to their capacity to afford a real clinical benefit in terms of patient's survival. Essential to ICpI success is the presence of tumor-associated neoantigens generated by non-synonymous mutations, since a direct relationship between mutation load of malignant cells and susceptibility to ICpI has been confidently established. However, it has been also suggested that high intratumor heterogeneity (ITH) associated with subclonal neoantigens could not elicit adequate immune responses. Several years ago we discovered that in vivo treatment of leukemic mice with triazene compounds (TZC) produces a marked increase of leukemia cell immunogenicity [a phenomenon termed Drug-Induced Xenogenization (DIX)] through point mutations able to generate strong tumor neoantigens (Drug-Induced Neoantigens, DIN). Immunogenic mutations are produced by TZC-dependent methylation of O6-guanine of DNA, that is suppressed by the DNA repair protein methyl-guaninemethyltransferase (MGMT). This minireview illustrates preclinical investigations conducted in animal models where DIN-positive murine leukemia cells were inoculated intracerebrally into histocompatible mice. The analysis of the literature indicates that the growth of xenogenized malignant cells is controlled by anti-DIN graft responses and by intra-cerebral or intravenous adoptive transfer of anti-DIN cytotoxic T lymphocytes. This survey reminds also that PARP inhibitors increase substantially the antitumor activity of TZC and can be administered with the intent of suppressing more efficiently tumor load and possibly reducing ITH through downsizing the polyclonality of xenogenized tumor cell population. Finally, the present report illustrates a hypothetical clinical protocol that could be considered as an example of future development of DIXbased tumor immuno-chemotherapy in brain malignancies. The protocol involves oral or intravenous administration of TZC along with loco-regional (i.e. intracerebral "wafer") treatment with agents able to increase tumor cell sensitivity to the cytotoxic and xenogenizing effects of TZC (i.e. MGMT and PARP inhibitors) without enhancing the systemic toxicity of these DNA methylating compounds.

Franzese, O., Battaini, F., Graziani, G., Tentori, L., Barbaccia, M.l., Aquino, A., et al. (2018). Drug-induced xenogenization of tumors: A possible role in the immune control of malignant cell growth in the brain?. PHARMACOLOGICAL RESEARCH, 131, 1-6 [10.1016/j.phrs.2018.03.005].

Drug-induced xenogenization of tumors: A possible role in the immune control of malignant cell growth in the brain?

Franzese O.;Battaini F.;Graziani G.;Tentori L.;Barbaccia M. L.;Aquino A.;Roselli M.;Bonmassar E.;Torino F.
2018-01-01

Abstract

In recent years, immune checkpoint inhibitors (ICpI) have provided the ground to bring tumor immunity back to life thanks to their capacity to afford a real clinical benefit in terms of patient's survival. Essential to ICpI success is the presence of tumor-associated neoantigens generated by non-synonymous mutations, since a direct relationship between mutation load of malignant cells and susceptibility to ICpI has been confidently established. However, it has been also suggested that high intratumor heterogeneity (ITH) associated with subclonal neoantigens could not elicit adequate immune responses. Several years ago we discovered that in vivo treatment of leukemic mice with triazene compounds (TZC) produces a marked increase of leukemia cell immunogenicity [a phenomenon termed Drug-Induced Xenogenization (DIX)] through point mutations able to generate strong tumor neoantigens (Drug-Induced Neoantigens, DIN). Immunogenic mutations are produced by TZC-dependent methylation of O6-guanine of DNA, that is suppressed by the DNA repair protein methyl-guaninemethyltransferase (MGMT). This minireview illustrates preclinical investigations conducted in animal models where DIN-positive murine leukemia cells were inoculated intracerebrally into histocompatible mice. The analysis of the literature indicates that the growth of xenogenized malignant cells is controlled by anti-DIN graft responses and by intra-cerebral or intravenous adoptive transfer of anti-DIN cytotoxic T lymphocytes. This survey reminds also that PARP inhibitors increase substantially the antitumor activity of TZC and can be administered with the intent of suppressing more efficiently tumor load and possibly reducing ITH through downsizing the polyclonality of xenogenized tumor cell population. Finally, the present report illustrates a hypothetical clinical protocol that could be considered as an example of future development of DIXbased tumor immuno-chemotherapy in brain malignancies. The protocol involves oral or intravenous administration of TZC along with loco-regional (i.e. intracerebral "wafer") treatment with agents able to increase tumor cell sensitivity to the cytotoxic and xenogenizing effects of TZC (i.e. MGMT and PARP inhibitors) without enhancing the systemic toxicity of these DNA methylating compounds.
2018
Online ahead of print
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/14 - FARMACOLOGIA
English
Cancer immunotherapy; Cyclophosphamide (PubChem CID: 2907); DNA repair enzyme; DTIC (Dacarbazine) (PubChem CID: 5353562); Drug-induced neoantigens; GPI 15427 (PubChem CID: 11739525); Immune checkpoint inhibitors; Lomeguatrib (PubChem CID: 3025944); MGMT inhibitors; NU 1025 (PubChem CID: 63306); Temozolomide; Temozolomide (PubChem CID: 5394)
Franzese, O., Battaini, F., Graziani, G., Tentori, L., Barbaccia, M.l., Aquino, A., et al. (2018). Drug-induced xenogenization of tumors: A possible role in the immune control of malignant cell growth in the brain?. PHARMACOLOGICAL RESEARCH, 131, 1-6 [10.1016/j.phrs.2018.03.005].
Franzese, O; Battaini, F; Graziani, G; Tentori, L; Barbaccia, Ml; Aquino, A; Roselli, M; Fuggetta, Mp; Bonmassar, E; Torino, F
Articolo su rivista
File in questo prodotto:
File Dimensione Formato  
Pharmacological Reserach, online proof. 2018.pdf

solo utenti autorizzati

Licenza: Copyright dell'editore
Dimensione 389.38 kB
Formato Adobe PDF
389.38 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/195629
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 5
  • ???jsp.display-item.citation.isi??? 5
social impact