title: Immune-modulating effects of bevacizumab in metastatic non-small-cell lung cancer patients.
abstract: The mPEBev is an anticancer regimen which combines a chemotherapy doublet, based on cisplatin and oral etoposide (mPE), with bevacizumab (mPEBev), a mAb targeting the vasculo-endothelial growth factor (VEGF). In previous studies, this regimen showed powerful anti-angiogenetic effects and significant antitumor activity in metastatic non-small-cell lung cancer (mNSCLC) patients. We also recorded the best benefit in patients exhibiting low-systemic inflammatory profile at baseline. On these bases, we hypothesized that mPEBev antitumor activity could be partially related to bevacizumab-associated immunological effects. For this reason, we performed an immunological monitoring in 59 out of 120 stage IIIb-IV NSCLC patients enrolled in the BEVA2007 phase II trial, who received fractioned cisplatin (30 mg/sqm days 1-3q21) and oral etoposide (50 mg, days 1-15q21) (mPE doublet) ±bevacizumab. In this group of patients, 12 received the mPE doublet alone and 47 the doublet in combination with bevacizumab (5 mg/kg on the day 3q21; mPEBev regimen). Blood cell counts, serum analysis, multiplex cytokine assay and immunocytofluorimetric analysis, performed on baseline and post-treatment on blood samples from these patients, revealed that bevacizumab addition to the doublet decreased levels of pro-angiogenic (VEGF, Angiostatin-1 and Follistatin) and inflammatory cytokines (interferon (IFN)γ, IL4 and IL17), improvedin vivoandin vitrocytotoxic T-lymphocytes (CTL) response and promoted dendritic cell activation. These results suggest that the mPEBev regimen improve the micro-environmental conditions for an efficient antigen-specific CTL response, making it a feasible candidate regimen to be assessed in combination with immune-checkpoint inhibitors in NSCLC patients.
authors.affiliation: Radiotherapy Unit, Department of Oncology, Siena University Hospital , Siena, Italy.
authors.forename: E C
authors.initials: EC
authors.lastname: Martino
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second Naples University , Naples, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Misso
authors.affiliation: Radiotherapy Unit, Department of Oncology, Siena University Hospital , Siena, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Pastina
authors.affiliation: CROM, Mercogliano , Italy.
authors.forename: S
authors.initials: S
authors.lastname: Costantini
authors.affiliation: Radiotherapy Unit, Department of Oncology, Siena University Hospital , Siena, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Vanni
authors.affiliation: Microbiology and Virology Unit, Department of Medical Biotechnology , Siena, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Gandolfo
authors.affiliation: Medical Oncology Unit, 'Magna Graecia' University and AUO 'Materdomini' , Catanzaro, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Botta
authors.affiliation: CROM, Mercogliano , Italy.
authors.forename: F
authors.initials: F
authors.lastname: Capone
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second Naples University , Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Lombardi
authors.affiliation: Radiotherapy Unit, Department of Oncology, Siena University Hospital , Siena, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Pirtoli
authors.affiliation: Medical Oncology Unit, 'Magna Graecia' University and AUO 'Materdomini' , Catanzaro, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Tassone
authors.affiliation: Department of Science of Life; University of Siena , Siena, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ulivieri
authors.affiliation: Medical Oncology Unit, 'Magna Graecia' University and AUO 'Materdomini' , Catanzaro, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Tagliaferri
authors.affiliation: Microbiology and Virology Unit, Department of Medical Biotechnology , Siena, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Cusi
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second Naples University , Naples, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Caraglia
authors.affiliation: Radiotherapy Unit, Department of Oncology, Siena University Hospital , Siena, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Correale