Publications by authors named "Michele Maio"

188 Publications

Tremelimumab plus durvalumab retreatment and 4-year outcomes in patients with mesothelioma: a follow-up of the open label, non-randomised, phase 2 NIBIT-MESO-1 study.

Lancet Respir Med 2021 Apr 9. Epub 2021 Apr 9.

Center for Immuno-Oncology, Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Siena, Italy; EPigenetic Immune-Oncology Consortium Airc (EPICA), Rome, Italy; Department of Medicine, Surgery, and Neuroscience, University of Siena, Siena, Italy; Fondazione Italian Network for Tumour Biotherapy (NIBIT) Onlus, Siena, Italy. Electronic address:

Background: The NIBIT-MESO-1 study demonstrated the efficacy and safety of tremelimumab combined with durvalumab in patient with unresectable mesothelioma followed up for a median of 52 months [IQR 49-53]. Here, we report 4-year survival and outcomes after retreatment, and the role of tumour mutational burden (TMB) in identifying patients who might have a better outcome in response to combined therapy.

Methods: NIBIT-MESO-1 was an open-label, non-randomised, phase 2 trial of patients with unresectable pleural or peritoneal mesothelioma who received intravenous tremelimumab (1 mg/kg bodyweight) and durvalumab (20 mg/kg bodyweight) every 4 weeks for four doses, followed by maintenance intravenous durvalumab at the same dose and schedule for nine doses. In this follow-up study, patients with disease progression following initial clinical benefit-ie, a partial repsonse or stable disease-were eligible for retreatment and with the same doses and schedules for tremelimumab and durvalumab as used in the NIBIT-MESO-1 trial. The primary endpoint, immune-related objective response rate, was evaluated per immune-related modified Response Evaluation Criteria in Solid Tumors (RECIST) or immune-related RECIST 1.1 criteria for patients with pleural or peritoneal malignant mesothelioma, respectively. Key secondary endpoints were overall survival and safety, and TMB was also evaluated post hoc in patients who had tumour tissue available before treatment. The intention-to-treat population was used for analysis of all efficacy endpoints. This study is registered with ClinicalTrials.gov, number NCT02588131.

Findings: 40 patients were enrolled in the NIBIT-MESO-1 study between Oct 30, 2015, and Oct 12, 2016. At data cut-off, April 30, 2020, five (13%) of 40 patients were alive, and 35 (88%) patients had died of progressive disease. At a median follow-up of 52 months (IQR 49-53), median overall survival was 16·5 months (95% CI 13·7-19·2). Survival was 20% (eight of 40 patients) at 36 months and 15% (six of 40 patients) and 48 months. 17 (43%) of 40 patients met the criteria for enrolment in the retreatment study and were retreated with at least one dose of tremelimumab and durvalumab. No immune-related objective responses were observed in the 17 retreated patients. Seven (41%) of 17 patients achieved immune-related stable disease. From the start of retreatment to a median follow-up of 24 months (22·0-25·0), median overall survival was 12·5 months (95% CI 0·0-25·8), and survival at 12 months was 52·9%, at 18 months was 35·3%, and at 24 months was 23·5%. There were no grade 3-4 immune-related adverse events in the retreatment cohort. In a post-hoc analysis of 28 patients for whom tumour tissue before treatment was available, patients with a TMB higher than the median value of 8·3 mutations per Mb had a higher median overall survival compared with patients with TMB below the median value, but this difference was non-significant. Moreover, when patients were additionally stratified for ICI retreatment (n=13), there was a significant difference in survival between those with a TMB higher than the median of 8·3 mutations per Mb and those with TMB lower than the median in the retreated cohort (41·3 months vs 17·4 months; p=0·02).

Interpretation: Tremelimumab combined with durvalumab was associated with long-term survival in patients with mesothelioma. Retreatment was safe and resulted in clinically meaningful outcomes, thus suggesting its potential application in the clinical practice of mesothalioma patients.

Funding: NIBIT Foundation, Fondazione AIRC, AstraZeneca.
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http://dx.doi.org/10.1016/S2213-2600(21)00043-6DOI Listing
April 2021

Back to simplicity: a four-marker blood cell score to quantify prognostically relevant myeloid cells in melanoma patients.

J Immunother Cancer 2021 Feb;9(2)

Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background: Myeloid-derived suppressor cells (MDSC), a cornerstone of cancer-related immunosuppression, influence response to therapy and disease outcomes in melanoma patients. Nevertheless, their quantification is far from being integrated into routine clinical practice mostly because of the complex and still evolving phenotypic signatures applied to define the cell subsets. Here, we used a multistep downsizing process to verify whether a core of few markers could be sufficient to capture the prognostic potential of myeloid cells in peripheral blood mononuclear cells (PBMC) of metastatic melanoma patients.

Methods: In baseline frozen PBMC from a total of 143 stage IIIc to IV melanoma patients, we first assessed the relevant or redundant expression of myeloid and MDSC-related markers by flow cytometry (screening set, n=23 patients). Subsequently, we applied the identified panel to the development set samples (n=59 patients undergoing first/second-line therapy) to obtain prognostic variables associated with overall survival (OS) and progression-free survival (PFS) by machine learning adaptive index modeling. Finally, the identified score was confirmed in a validation set (n=61) and compared with standard clinical prognostic factors to assess its additive value in patient prognostication.

Results: This selection process led to the identification of what we defined myeloid index score (MIS), which is composed by four cell subsets (CD14, CD14HLA-DR, CD14PD-L1 and CD15 cells), whose frequencies above cut-offs stratified melanoma patients according to progressively worse prognosis. Patients with a MIS=0, showing no over-threshold value of MIS subsets, had the best clinical outcome, with a median survival of >33.6 months, while in patients with MIS 1→3, OS deteriorated from 10.9 to 6.8 and 6.0 months as the MIS increased (p<0.0001, c-index=0.745). MIS clustered patients into risk groups also according to PFS (p<0.0001). The inverse correlation between MIS and survival was confirmed in the validation set, was independent of the type of therapy and was not interfered by clinical prognostic factors. MIS HR was remarkably superior to that of lactate dehydrogenase, tumor burden and neutrophil-to-lymphocyte ratio.

Conclusion: The MIS >0 identifies melanoma patients with a more aggressive disease, thus acting as a simple blood biomarker that can help tailoring therapeutic choices in real-life oncology.
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http://dx.doi.org/10.1136/jitc-2020-001167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887358PMC
February 2021

Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial.

Lancet Oncol 2020 11 19;21(11):1465-1477. Epub 2020 Sep 19.

Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.

Background: Previously, findings from CheckMate 238, a double-blind, phase 3 adjuvant trial in patients with resected stage IIIB-C or stage IV melanoma, showed significant improvements in recurrence-free survival and distant metastasis-free survival with nivolumab versus ipilimumab. This report provides updated 4-year efficacy, initial overall survival, and late-emergent safety results.

Methods: This multicentre, double-blind, randomised, controlled, phase 3 trial was done in 130 academic centres, community hospitals, and cancer centres across 25 countries. Patients aged 15 years or older with resected stage IIIB-C or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive nivolumab or ipilimumab via an interactive voice response system and stratified according to disease stage and baseline PD-L1 status of tumour cells. Patients received intravenous nivolumab 3 mg/kg every 2 weeks or intravenous ipilimumab 10 mg/kg every 3 weeks for four doses, and then every 12 weeks until 1 year of treatment, disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was recurrence-free survival by investigator assessment, and overall survival was a key secondary endpoint. Efficacy analyses were done in the intention-to-treat population (all randomly assigned patients). All patients who received at least one dose of study treatment were included in the safety analysis. The results presented in this report reflect the 4-year update of the ongoing study with a database lock date of Jan 30, 2020. This study is registered with ClinicalTrials.gov, NCT02388906.

Findings: Between March 30 and Nov 30, 2015, 906 patients were assigned to nivolumab (n=453) or ipilimumab (n=453). Median follow-up was 51·1 months (IQR 41·6-52·7) with nivolumab and 50·9 months (36·2-52·3) with ipilimumab; 4-year recurrence-free survival was 51·7% (95% CI 46·8-56·3) in the nivolumab group and 41·2% (36·4-45·9) in the ipilimumab group (hazard ratio [HR] 0·71 [95% CI 0·60-0·86]; p=0·0003). With 211 (100 [22%] of 453 patients in the nivolumab group and 111 [25%] of 453 patients in the ipilimumab group) of 302 anticipated deaths observed (about 73% of the originally planned 88% power needed for significance), 4-year overall survival was 77·9% (95% CI 73·7-81·5) with nivolumab and 76·6% (72·2-80·3) with ipilimumab (HR 0·87 [95% CI 0·66-1·14]; p=0·31). Late-emergent grade 3-4 treatment-related adverse events were reported in three (1%) of 452 and seven (2%) of 453 patients. The most common late-emergent treatment-related grade 3 or 4 adverse events reported were diarrhoea, diabetic ketoacidosis, and pneumonitis (one patient each) in the nivolumab group, and colitis (two patients) in the ipilimumab group. Two previously reported treatment-related deaths in the ipilimumab group were attributed to study drug toxicity (marrow aplasia in one patient and colitis in one patient); no further treatment-related deaths were reported.

Interpretation: At a minimum of 4 years' follow-up, nivolumab demonstrated sustained recurrence-free survival benefit versus ipilimumab in resected stage IIIB-C or IV melanoma indicating a long-term treatment benefit with nivolumab. With fewer deaths than anticipated, overall survival was similar in both groups. Nivolumab remains an efficacious adjuvant treatment for patients with resected high-risk melanoma, with a safety profile that is more tolerable than that of ipilimumab.

Funding: Bristol Myers Squibb and Ono Pharmaceutical.
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http://dx.doi.org/10.1016/S1470-2045(20)30494-0DOI Listing
November 2020

Multicenter International Society for Immunotherapy of Cancer Study of the Consensus Immunoscore for the Prediction of Survival and Response to Chemotherapy in Stage III Colon Cancer.

J Clin Oncol 2020 11 8;38(31):3638-3651. Epub 2020 Sep 8.

Princess Margaret Cancer Centre, UHN, Toronto, Ontario, Canada.

Purpose: The purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR).

Methods: An international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy.

Results: Patients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high low], 0.48; 95% CI, 0.32 to 0.71; = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high low], 0.41; 95% CI, 0.25 to 0.67; .0003) of patient's sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR [high low], 0.36; 95% CI, 0.21 to 0.62; .0003). Immunoscore had the strongest contribution χ2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; = .0011) and high-risk (HR [chemotherapy no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; = .0015) patients, in contrast to the low-Immunoscore group ( > .12).

Conclusion: This study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.
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http://dx.doi.org/10.1200/JCO.19.03205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605397PMC
November 2020

Immune Checkpoint Inhibitors for Cancer Therapy in the COVID-19 Era.

Clin Cancer Res 2020 08 15;26(16):4201-4205. Epub 2020 Jun 15.

Center for Immuno-Oncology, Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Siena, Italy.

The potential immune intersection between COVID-19 disease and cancer therapy raises important practical clinical questions and highlights multiple scientific gaps to be filled. Among available therapeutic approaches to be considered, immune checkpoint inhibitors (ICI) seem to require major attention as they may act at the crossroads between cancer treatment and COVID-19 disease, due to their profound immunomodulatory activity. On the basis of available literature evidence, we suggest guidance to consider for treating physicians, and propose areas of clinical and preclinical investigation. Comprehensively, although with the necessary caution, ICI therapy seems to remain a suitable therapeutic option for patients with cancer during the COVID-19 pandemic.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1657DOI Listing
August 2020

Overall survival at 5 years of follow-up in a phase III trial comparing ipilimumab 10 mg/kg with 3 mg/kg in patients with advanced melanoma.

J Immunother Cancer 2020 06;8(1)

Center for Immuno-Oncology, University Hospital of Siena, Instituto Toscano Tumori, Siena, Italy.

Background: We have previously reported significantly longer overall survival (OS) with ipilimumab 10 mg/kg versus ipilimumab 3 mg/kg in patients with advanced melanoma, with higher incidences of adverse events (AEs) at 10 mg/kg. This follow-up analysis reports a 5-year update of OS and safety.

Methods: This randomized, multicenter, double-blind, phase III trial included patients with untreated or previously treated unresectable stage III or IV melanoma. Patients were randomly assigned (1:1) to ipilimumab 10 mg/kg or 3 mg/kg every 3 weeks for 4 doses. The primary end point was OS.

Results: At a minimum follow-up of 61 months, median OS was 15.7 months (95% CI 11.6 to 17.8) at 10 mg/kg and 11.5 months (95% CI 9.9 to 13.3) at 3 mg/kg (HR 0.84, 95% CI 0.71 to 0.99; p=0.04). In a subgroup analysis, median OS of patients with asymptomatic brain metastasis was 7.0 months (95% CI 4.0 to 12.8) in the 10 mg/kg group and 5.7 months (95% CI 4.2 to 7.0) in the 3 mg/kg group. In patients with wild-type or mutant tumors, median OS was 13.8 months (95% CI 10.2 to 17.0) and 33.2 months (95% CI 19.4 to 45.2) in the 10 mg/kg group, and 11.2 months (95% CI 9.2 to 13.8) and 19.7 months (95% CI 11.6 to 25.3) in the 3 mg/kg group, respectively. The incidence of grade 3/4 treatment-related AEs was 36% in the 10 mg/kg group vs 20% in the 3 mg/kg group, and deaths due to treatment-related AEs occurred in four (1%) and two patients (1%), respectively.

Conclusions: This 61-month follow-up of a phase III trial showed sustained long-term survival in patients with advanced melanoma who started metastatic treatment with ipilimumab monotherapy, and confirmed the significant benefit for those who received ipilimumab 10 mg/kg vs 3 mg/kg. These results suggest the emergence of a plateau in the OS curve, consistent with previous ipilimumab studies.

Trial Registration Number: NCT01515189.
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http://dx.doi.org/10.1136/jitc-2019-000391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279645PMC
June 2020

Loss of Spry1 reduces growth of BRAF-mutant cutaneous melanoma and improves response to targeted therapy.

Cell Death Dis 2020 05 22;11(5):392. Epub 2020 May 22.

Immunopathology and Cancer Biomarkers, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.

Mitogen-activated protein kinase (MAPK) pathway activation is a central step in BRAF-mutant cutaneous melanoma (CM) pathogenesis. In the last years, Spry1 has been frequently described as an upstream regulator of MAPK signaling pathway. However, its specific role in BRAF-mutant CM is still poorly defined. Here, we report that Spry1 knockdown (Spry1) in three BRAF-mutant CM cell lines markedly induced cell cycle arrest and apoptosis, repressed cell proliferation in vitro, and impaired tumor growth in vivo. Furthermore, our findings indicated that Spry1 reduced the expression of several markers of epithelial-mesenchymal transition, such as MMP-2 both in vitro and in vivo. These effects were associated with a sustained and deleterious phosphorylation of ERK1/2. In addition, p38 activation along with an increase in basal ROS levels were found in Spry1 clones compared to parental CM cell lines, suggesting that BRAF-mutant CM may restrain the activity of Spry1 to avoid oncogenic stress and to enable tumor growth. Consistent with this hypothesis, treatment with the BRAF inhibitor (BRAFi) vemurafenib down-regulated Spry1 levels in parental CM cell lines, indicating that Spry1 expression is sustained by the MAPK/ERK signaling pathway in a positive feedback loop that safeguards cells from the potentially toxic effects of ERK1/2 hyperactivation. Disruption of this feedback loop rendered Spry1 cells more susceptible to apoptosis and markedly improved response to BRAFi both in vitro and in vivo, as a consequence of the detrimental effect of ERK1/2 hyperactivation observed upon Spry1 abrogation. Therefore, targeting Spry1 might offer a treatment strategy for BRAF-mutant CM by inducing the toxic effects of ERK-mediated signaling.
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http://dx.doi.org/10.1038/s41419-020-2585-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244546PMC
May 2020

SARS-COV-2 infection in patients with cancer undergoing checkpoint blockade: Clinical course and outcome.

Eur J Cancer 2020 07 3;133:1-3. Epub 2020 May 3.

Center for Immuno-Oncology, Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Siena, Italy; NIBIT Foundation Onlus, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2020.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196405PMC
July 2020

Challenges in lung cancer therapy during the COVID-19 pandemic.

Lancet Respir Med 2020 06 9;8(6):542-544. Epub 2020 Apr 9.

Center for Immuno-Oncology, Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, 53100 Siena, Italy; NIBIT Foundation Onlus, Siena, Italy. Electronic address:

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http://dx.doi.org/10.1016/S2213-2600(20)30170-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146673PMC
June 2020

Permanent diabetes insipidus in a patient with mesothelioma treated with immunotherapy.

Arch Endocrinol Metab 2020 Aug 6;64(4):483-486. Epub 2020 Apr 6.

Unit of Endocrinology, Department of Medical, Surgical and Neurological Sciences, University Hospital of Siena, Siena, Italy.

Checkpoint inhibitors have substantially improved the prognosis for patients with advanced malignancy. Treatment with immunomodulants has the ability to reactivate the immune system against tumor cells, but can also trigger the development of immune-related adverse events that reflects a loss of tolerance of the immune system for self-antigens. Regarding the endocrine system, thyroid and pituitary are the most frequent glands involved; in particular hypophysitis is commonly observed with anti-CTLA4 with a variable impaired anterior pituitary dysfunction (mainly ACTH and TSH dysregulation) while a posterior pituitary dysfunction has been rarely described. A 68-year-old man with a diagnosis of metastatic mesothelioma started in September 2016 first-line treatment with tremelimumab and durvalumab. After 3 cycles he presented sudden onset of polydipsia and polyuria without other symptoms. Diagnostic work-up, including a water deprivation test, established a diagnosis of central diabetes insipidus. Patient started sublingual desmopressin 60 mcg three times a day, that was subsequently increased up to 480 mcg/die. At magnetic resonance imaging the posterior lobe of pituitary gland did not show high signal intensity on T1-weighted images. After regression of diabetes insipidus symptoms under desmopressin, patient restarted cancer treatment and received additional 10 doses without worsening of endocrinological toxicity or further treatment-related toxicities, maintaining the same desmopressin dosage. Posterior pituitary dysfunction has been rarely observed in patients treated with immunomodulants. To our knowledge, this is the first observation of permanent central diabetes insipidus in patients treated with combined immune checkpoint inhibitors (tremelimumab and durvalumab).
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http://dx.doi.org/10.20945/2359-3997000000221DOI Listing
August 2020

Serafino Zappacosta: An Enlightened Mentor and Educator.

Front Immunol 2020 13;11:217. Epub 2020 Feb 13.

Dipartimento di Scienze Mediche Traslazionali, Università di Napoli "Federico II", Naples, Italy.

With this article, the authors aim to honor the memory of Serafino Zappacosta, who had been their mentor during the early years of their career in science. The authors discuss how the combination of Serafino Zappacosta's extraordinary commitment to teaching and passion for science created a fostering educational environment that led to the creation of the "." The review also illustrates how the research on the MHC and the inspirational scientific context in the Zappacosta's laboratory influenced the authors' early scientific interests, and subsequent professional work as immunologists.
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http://dx.doi.org/10.3389/fimmu.2020.00217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031500PMC
March 2021

Circulating Levels of PD-L1 in Mesothelioma Patients from the NIBIT-MESO-1 Study: Correlation with Survival.

Cancers (Basel) 2020 Feb 5;12(2). Epub 2020 Feb 5.

Center for Immuno-Oncology, Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, 53100 Siena, Italy.

Targeting of the programmed cell death protein (PD)-1/programmed death-ligand 1 (PD-L1) axis has shown a significant clinical impact in several tumor types. Accordingly, our phase II NIBIT-MESO-1 study demonstrated an improved clinical efficacy in mesothelioma patients treated with the anti-PD-L1 durvalumab combined with the anti-cytotoxic T-lymphocyte antigen (CTLA)-4 tremelimumab, as compared to tremelimumab alone. Due to the promising therapeutic activity of immune check-point inhibitors (ICIs) in mesothelioma patients, the identification of biomarkers predictive of response to treatment is of crucial relevance. The prognostic role of soluble PD-L1 (sPD-L1) proposed in cancer patients prompted us to investigate this protein in sera from mesothelioma patients ( = 40) enrolled in the NIBIT-MESO-1 study. A significant ( < 0.001) increase in sPD-L1 levels was detected in patients after the first cycle and during therapy vs. baseline. A longer overall survival (OS) was observed in patients with sPD-L1 concentrations below (at baseline, d1C2, d1C5 ( < 0.01)) or FC values above ( < 0.05 at d1C2, d1C3, d1C5) their statistically calculated optimal cut-offs. On the basis of these initial results, the specific role of CTLA-4-, PD-L1-, or PD-1-targeting on sPD-L1 release was then investigated in sera from 81 additional ICI-treated solid cancer patients. Results showed a significant ( < 0.001) increase of sPD-L1 levels during therapy compared to baseline only in anti-PD-L1-treated patients, supporting the specific involvement of PD-L1 targeting in the release of its soluble form. Our findings suggest that sPD-L1 represents a predictive biomarker of clinical response to anti-PD-L1 cancer immunotherapy.
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http://dx.doi.org/10.3390/cancers12020361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072596PMC
February 2020

Prognostic clinical factors in patients affected by non-small-cell lung cancer receiving Nivolumab.

Expert Opin Biol Ther 2020 03 6;20(3):319-326. Epub 2020 Feb 6.

Unit of Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.

: Immune-checkpoint inhibitors have radically changed the treatment landscape of Non-Small-Cell Lung Cancer (NSCLC). It is still unclear whether specific clinical characteristics might identify those patients benefiting from immunotherapy more than others. The aim of this study was to identify clinical characteristics associated with disease-specific survival (DSS), time-to-treatment failure (TTF), objective responses (OR) and progressive disease (PD) in NSCLC patients treated with Nivolumab.: This was a multicenter retrospective study conducted on 294 patients treated with Nivolumab for advanced NSCLC.: Of the more than 50 variables analyzed, five showed a significant correlation with DSS: ECOG PS, size of the biggest brain metastasis, number of metastatic sites, toxicity, and malignant pleural effusion. Three variables significantly correlated with TTF: malignant pleural effusion, number of metastatic sites, number of liver metastases. Malignant pleural effusion was the only variable showing a significant correlation with OR, as well as the only one correlating with all the endpoints of the study.: This study identified clinical characteristics associated with survival and response during treatment with Nivolumab in NSCLC patients. The unfavorable association between malignant pleural effusion and objective response is a novel finding with important translational implications.
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http://dx.doi.org/10.1080/14712598.2020.1724953DOI Listing
March 2020

Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and Outcomes with Nivolumab in Pretreated Non-Small Cell Lung Cancer (NSCLC): A Large Retrospective Multicenter Study.

Adv Ther 2020 03 30;37(3):1145-1155. Epub 2020 Jan 30.

Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy.

Introduction: Immune checkpoint inhibitors have provided substantial benefit in non-small cell lung cancer (NSCLC) with unprecedented results in terms of survival. However, the identification of reliable predictive biomarkers to these agents is lacking and multiple clinicopathological factors have been evaluated. The aim of this study was to analyze the potential role of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) levels in patients with pretreated NSCLC receiving nivolumab.

Methods: This was a retrospective multicenter study involving 14 Italian centers, evaluating the role of some laboratory results in patients with NSCLC treated with nivolumab in the second or later lines of therapy for at least four doses and with a disease re-staging.

Results: A total of 187 patients with available pretreatment laboratory results were included. NLR levels below 5 were associated with an improvement in terms of both progression-free survival (PFS) (p = 0.028) and overall survival (OS) (p = 0.001), but not in terms of overall response rate (ORR) or disease control rate (DCR). Moreover, PLR levels below 200 were associated with longer PFS (p = 0.0267) and OS (p = 0.05), as well as higher ORR (p = 0.04) and DCR (p = 0.001). In contrast, LDH levels above the upper normal limit (UNL) were not associated with significant impact on patient outcomes.

Conclusions: Patients with pretreated NSCLC and high pretreatment levels of NLR and PLR may experience inferior outcomes with nivolumab. Therefore, in this subgroup of patients with poor prognosis the use of alternative therapeutic strategies may be a valuable option, especially in programmed cell death ligand 1 (PD-L1)-negative patients and/or in the presence of other additional poor prognostic factors.
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http://dx.doi.org/10.1007/s12325-020-01229-wDOI Listing
March 2020

Immunotherapy of brain metastases: breaking a "dogma".

J Exp Clin Cancer Res 2019 Oct 17;38(1):419. Epub 2019 Oct 17.

Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Viale Bracci, 14, 53100, Siena, Italy.

Until very few years ago, the oncology community dogmatically excluded any clinical potential for immunotherapy in controlling brain metastases. Therefore, despite the significant therapeutic efficacy of monoclonal antibodies to immune check-point(s) across a wide range of tumor types, patients with brain disease were invariably excluded from clinical trials with these agents. Recent insights on the immune landscape of the central nervous system, as well as of the brain tumor microenvironment, are shedding light on the immune-biology of brain metastases.Interestingly, retrospective analyses, case series, and initial prospective clinical trials have recently investigated the role of different immune check-point inhibitors in brain metastases, reporting a significant clinical activity also in this subset of patients. These findings, and their swift translation in the daily practice, are driving fundamental changes in the clinical management of patients with brain metastases, and raise important neuroradiologic challenges. Along this line, neuro-oncology undoubtedly represents an additional area of active investigation and of growing interest to support medical oncologists in the evaluation of clinical responses of brain metastases to ICI treatment, and in the management of neurologic immune-related adverse events.Aim of this review is to summarize the most recent findings on brain metastases immunobiology, on the evolving scenario of clinical efficacy of ICI therapy in patients with brain metastases, as well as on the increasing relevance of neuroradiology in this therapeutic setting.
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http://dx.doi.org/10.1186/s13046-019-1426-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798349PMC
October 2019

Safety and efficacy of nivolumab in challenging subgroups with advanced melanoma who progressed on or after ipilimumab treatment: A single-arm, open-label, phase II study (CheckMate 172).

Eur J Cancer 2019 11 30;121:144-153. Epub 2019 Sep 30.

Department of Medical Oncology, Mount Vernon Cancer Centre, London, United Kingdom.

Background: Limited data are available on nivolumab in challenging subgroups with advanced melanoma. We report outcomes of nivolumab after prior ipilimumab in patients who are typically excluded from clinical trials.

Patients And Methods: In this phase II, single-arm, open-label, multicentre study (CheckMate 172), patients with advanced melanoma who progressed on or after ipilimumab received nivolumab 3 mg/kg, every 2 weeks for up to 2 years. The primary objective was incidence of grade ≥3, treatment-related select adverse events (AEs).

Results: At a minimum follow-up of 18 months, grade ≥3 treatment-related select AEs with the most variation across subgroups were diarrhoea and colitis (1.1% [n = 11] and 0.3% [n = 3] for the total population [n = 1008]; 0.6% [n = 1] and 0.6% [n = 1] for patients with an asymptomatic central nervous system [CNS] metastasis [n = 165; 16.4%]; 4.5% [n = 3] and 3.0% [n = 2] for patients with an Eastern Cooperative Oncology Group performance status [ECOG PS] of 2 [n = 66; 6.5%]; 2.4% [n = 2] and 0% for those who experienced a grade 3/4 immune-related AE [irAE] with prior ipilimumab [n = 84; 8.3%]; and 0% and 0% for autoimmune disease [n = 25; 2.5%], respectively). Median overall survival was 21.4 months in the total population and was 11.6, 2.4, 21.5, and 18.6 months in patients with a CNS metastasis, ECOG PS 2, a grade 3/4 irAE with prior ipilimumab, and autoimmune disease, respectively.

Conclusions: In this large, phase II clinical trial of patients with advanced melanoma who progressed on or after ipilimumab, nivolumab demonstrated a safety profile consistent with that of prior clinical trials. ClinicalTrials.gov ID: NCT02156804.
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http://dx.doi.org/10.1016/j.ejca.2019.08.014DOI Listing
November 2019

Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.

N Engl J Med 2019 10 28;381(16):1535-1546. Epub 2019 Sep 28.

From the Royal Marsden NHS Foundation Trust, London (J.L.), and the College of Medicine, Swansea University, Swansea (J.W.) - both in the United Kingdom; the Oncology Institute of Veneto IRCCS, Padua (V.C.-S.), the European Institute of Oncology, IRCCS, Milan (P.F.F.), Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples (P.A.A.), the Immunotherapy and Somatic Cell Therapy Unit, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (M.G.), and the Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital, Siena (M.M.) - all in Italy; the University of Colorado Cancer Center, Aurora (R.G.); Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille Hôpital Timone, Marseille (J.-J.G.), and Université de Paris, INSERM Unité 976, Assistance Publique-Hôpitaux de Paris Dermatology and Centres d'Investigation Clinique, Saint Louis Hospital, Paris (C.L.) - both in France; the Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland (P.R.); the University of Michigan, Ann Arbor (C.D.L.); Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas (C.L.C.); the Department of Dermatology, University of Essen, Essen, and the German Cancer Consortium, Heidelberg - both in Germany (D.S.); Universitäts Spital, Zurich, Switzerland (R.D.); Cross Cancer Institute, Edmonton, AB (M.S.), and the Princess Margaret Cancer Centre, Toronto (D.H.) - both in Canada; Tasman Oncology Research, Southport, QLD (A.H.), the Crown Princess Mary Cancer Centre, Melanoma Institute Australia, University of Sydney, Sydney, NSW (M.S.C., G.V.L.), and the Royal North Shore and Mater Hospitals (G.V.L.), Sydney, and the Peter MacCallum Cancer Centre, Melbourne, VIC (G.M.) - all in Australia; General University Hospital Gregorio Marañon and Centro de Investigación Biomédica en Red de Oncología, Madrid (I.M.-R.); the Netherlands Cancer Institute, Amsterdam (J.H.); the Leuven Cancer Institute, Department of General Medical Oncology, University Hospital Leuven, Leuven, Belgium (P.S.); University of California San Diego Health-La Jolla Moores Cancer Center, La Jolla (G.A.D.); the Department of Oncology, Odense University Hospital, Odense, Denmark (L.B.); Bristol-Myers Squibb, Princeton, NJ (J.I.R., A.B., A.M.); Dana-Farber Cancer Institute, Boston (F.S.H.); and the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (J.D.W.).

Background: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial.

Methods: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group.

Results: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted.

Conclusions: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).
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http://dx.doi.org/10.1056/NEJMoa1910836DOI Listing
October 2019

Guadecitabine Plus Ipilimumab in Unresectable Melanoma: The NIBIT-M4 Clinical Trial.

Clin Cancer Res 2019 12 17;25(24):7351-7362. Epub 2019 Sep 17.

Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy.

Purpose: The immunomodulatory activity of DNA hypomethylating agents (DHAs) suggests they may improve the effectiveness of cancer immunotherapies. The phase Ib NIBIT-M4 trial tested this hypothesis using the next-generation DHA guadecitabine combined with ipilimumab.

Patients And Methods: Patients with unresectable stage III/IV melanoma received escalating doses of guadecitabine 30, 45, or 60 mg/m/day subcutaneously on days 1 to 5 every 3 weeks, and ipilimumab 3 mg/kg intravenously on day 1 every 3 weeks, starting 1 week after guadecitabine, for four cycles. Primary endpoints were safety, tolerability, and MTD of treatment; secondary were immune-related (ir) disease control rate (DCR) and objective response rate (ORR); and exploratory were changes in methylome, transcriptome, and immune contextures in sequential tumor biopsies, and pharmacokinetics.

Results: Nineteen patients were treated; 84% had grade 3/4 adverse events, and neither dose-limiting toxicities per protocol nor overlapping toxicities were observed. Ir-DCR and ir-ORR were 42% and 26%, respectively. Median CpG site methylation of tumor samples ( = 8) at week 4 (74.5%) and week 12 (75.5%) was significantly ( < 0.05) lower than at baseline (80.3%), with a median of 2,454 (week 4) and 4,131 (week 12) differentially expressed genes. Among the 136 pathways significantly ( < 0.05; Z score >2 or ←2) modulated by treatment, the most frequently activated were immune-related. Tumor immune contexture analysis ( = 11) demonstrated upregulation of HLA class I on melanoma cells, an increase in CD8, PD-1 T cells and in CD20 B cells in posttreatment tumor cores.

Conclusions: Treatment of guadecitabine combined with ipilimumab is safe and tolerable in advanced melanoma and has promising immunomodulatory and antitumor activity.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1335DOI Listing
December 2019

Safety and efficacy of nivolumab in patients with rare melanoma subtypes who progressed on or after ipilimumab treatment: a single-arm, open-label, phase II study (CheckMate 172).

Eur J Cancer 2019 09 21;119:168-178. Epub 2019 Aug 21.

Department of Dermatology, University Hospital Essen, Essen, and the German Cancer Consortium, Heidelberg, Germany.

Background: Nivolumab has been widely studied in non-acral cutaneous melanoma; however, limited data are available in other melanoma subtypes. We report outcomes by melanoma subtype in patients who received nivolumab after progression on prior ipilimumab.

Patients And Methods: CheckMate 172 was a phase II, single-arm, open-label, multicentre study that evaluated nivolumab in patients with advanced melanoma who progressed on or after ipilimumab. Patients received 3 mg/kg of nivolumab, every 2 weeks for up to 2 years. The primary end-point was incidence of grade ≥3, treatment-related select adverse events (AEs).

Results: Among 1008 treated patients, we report data on patients with non-acral cutaneous melanoma (n = 723 [71.7%]), ocular melanoma (n = 103 [10.2%]), mucosal melanoma (n = 63 [6.3%]), acral cutaneous melanoma (n = 55 [5.5%]) and other melanoma subtypes (n = 64 [6.3%]). There were no meaningful differences in the incidence of grade ≥3, treatment-related select AEs among melanoma subtypes or compared with the total population. No new safety signals emerged. At a minimum follow-up of 18 months, median overall survival was 25.3 months for non-acral cutaneous melanoma and 25.8 months for acral cutaneous melanoma, with 18-month overall survival rates of 57.5% and 59.0%, respectively. Median overall survival was 12.6 months for ocular melanoma and 11.5 months for mucosal melanoma, with 18-month overall survival rates of 34.8% and 31.5%, respectively.

Conclusions: The safety profile of nivolumab after ipilimumab is similar across melanoma subtypes. Compared with non-acral cutaneous melanoma, patients with acral cutaneous melanoma had similar survival outcomes, whereas those with ocular and mucosal melanoma had lower median overall survival. CLINICALTRIALS.

Gov Id: NCT02156804.
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http://dx.doi.org/10.1016/j.ejca.2019.07.010DOI Listing
September 2019

Adjuvant ipilimumab versus placebo after complete resection of stage III melanoma: long-term follow-up results of the European Organisation for Research and Treatment of Cancer 18071 double-blind phase 3 randomised trial.

Eur J Cancer 2019 09 7;119:1-10. Epub 2019 Aug 7.

Formerly at European Institute of Oncology, Milan, Italy.

Background: Since 2015, adjuvant therapy with ipilimumab is an approved treatment for stage III melanoma based on a significantly prolonged recurrence-free survival (RFS). At a median follow-up of 5.3 years, RFS, distant metastasis-free survival (DMFS) and overall survival (OS) were each significantly prolonged in the ipilimumab group compared with the placebo group, despite a 53.3% (ipilimumab) versus 4.6% (placebo) treatment discontinuation rate due to adverse events. We present now long-term follow-up results of this European Organisation for Research and Treatment of Cancer 18071 trial.

Patients, Methods And Results: A total of 99 sites randomised 951 patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes to receive intravenous infusions of ipilimumab 10 mg/kg or placebo, every 3 weeks for 4 doses, then every 3 months for up to 3 years. The RFS, DMFS and OS, as reported by the local investigators, were assessed by the intention-to-treat analysis. Among 431 patients randomised at 63 sites and who were still alive at the analysis reported in 2016, recent follow-up information could be obtained for 264 patients. The median OS follow-up was 6.9 years. The RFS (hazard ratio [HR] 0.75, 95% confidence interval 0.63-0.88; P < 0.001), DMFS (HR 0.76, 0.64-0.90; P = 0.002) and OS (HR 0.73, 0.60-0.89; P = 0.002) benefit observed in the ipilimumab group was durable with an 8.7% absolute difference at 7 years for OS. The benefit was consistent across subgroups.

Conclusions: Adjuvant therapy with ipilimumab prolongs RFS, DMFS and OS significantly. The benefit is sustained long term and consistent across subgroups.
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http://dx.doi.org/10.1016/j.ejca.2019.07.001DOI Listing
September 2019

The future of mesothelioma treatment: time to shift gear.

Lancet Respir Med 2019 07 15;7(7):554-555. Epub 2019 May 15.

Department of Oncology, Medical Oncology and Immunotherapy, Center for Immuno-Oncology, University Hospital of Siena, Siena 53100, Italy.

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http://dx.doi.org/10.1016/S2213-2600(19)30171-7DOI Listing
July 2019

The Effects of Conflict on Fertility: Evidence From the Genocide in Rwanda.

Demography 2019 06;56(3):935-968

University of Naples Federico II, Naples, Italy.

Our study analyzes the fertility effects of the 1994 genocide in Rwanda. We study the effects of violence on both the duration time to the first birth in the early post-genocide period and on the total number of post-genocide births per woman up to 15 years following the conflict. We use individual-level data from Demographic and Health Surveys, estimating survival and count data models. This article contributes to the literature on the demographic effects of violent conflict by testing two channels through which conflict influences fertility: (1) the type of violence exposure as measured by the death of a child or sibling, and (2) the conflict-induced change in local demographic conditions as captured by the change in the district-level sex ratio. Results indicate the genocide had heterogeneous effects on fertility, depending on the type of violence experienced by the woman, her age cohort, parity, and the time horizon (5, 10, and 15 years after the genocide). There is strong evidence of a child replacement effect. Having experienced the death of a child during the genocide increases both the hazard of having a child in the five years following the genocide and the total number of post-genocide births. Experiencing sibling death during the genocide significantly lowers post-genocide fertility in both the short-run and the long-run. Finally, a reduction in the local sex ratio negatively impacts the hazard of having a child in the five years following the genocide, especially for older women.
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http://dx.doi.org/10.1007/s13524-019-00780-8DOI Listing
June 2019

NK- and T-cell subsets in malignant mesothelioma patients: Baseline pattern and changes in the context of anti-CTLA-4 therapy.

Int J Cancer 2019 10 13;145(8):2238-2248. Epub 2019 May 13.

Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutet, Stockholm, Sweden.

Malignant mesothelioma (MM) is a highly aggressive form of cancer with limited treatment options. Although the role of NK cells has been studied in many solid tumors, the pattern of NK-cell subsets and their recognition of mesothelioma cells remain to be explored. We used RNA expression data of MM biopsies derived from the cancer genome atlas to evaluate the immune cell infiltrates. We characterized the phenotype of circulating NK and T cells of 27 MM patients before and after treatment with an anti-CTLA-4 antibody (tremelimumab). These immune cell profiles were compared to healthy controls. The RNA expression data of the MM biopsies indicated the presence of NK cells in a subgroup of patients. We demonstrated that NK cells recognize MM cell lines and that IL-15 stimulation improved NK cell-mediated lysis in vitro. Using multivariate projection models, we found that MM patients had a perturbed ratio of CD56 and CD56 NK subsets and increased serum concentrations of the cytokines IL-10, IL-8 and TNF-α. After tremelimumab treatment, the ratio between the CD56 and CD56 subsets shifted back towards physiological levels. Furthermore, the improved overall survival was correlated with low TIM-3 CD8 T-cell frequency, high DNAM-1 CD56 NK-cell frequency and high expression levels of NKp46 on the CD56 NK cells before and after immune checkpoint blockade. Together, our observations suggest that NK cells infiltrate MM and that they can recognize and kill mesothelioma cells. The disease is associated with distinct lymphocytes patterns, some of which correlate with prognosis or are affected by treatment with tremelimumab.
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http://dx.doi.org/10.1002/ijc.32363DOI Listing
October 2019

Genomic Features of Exceptional Response in Vemurafenib ± Cobimetinib-treated Patients with -mutated Metastatic Melanoma.

Clin Cancer Res 2019 06 1;25(11):3239-3246. Epub 2019 Mar 1.

Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, David Geffen UCLA School of Medicine, Los Angeles, California.

Purpose: Previous investigations identified transcriptional signatures associated with innate resistance to anti-programmed cell death protein 1 therapy in melanoma. This analysis aimed to increase understanding of the role of baseline genetic features in the variability of response to BRAF and MEK inhibitor therapy for -mutated metastatic melanoma.

Patients And Methods: This exploratory analysis compared genomic features, using whole-exome and RNA sequencing, of baseline tumors from patients who had complete response versus rapid progression (disease progression at first postbaseline assessment) on treatment with cobimetinib combined with vemurafenib or vemurafenib alone. Associations of gene expression with progression-free survival or overall survival were assessed by Cox proportional hazards modeling.

Results: Whole-exome sequencing showed that and alterations were more frequent in tumors from patients with rapid progression, while alterations were more frequent in tumors from patients with complete response. However, the low frequency of alterations in any one gene precluded their characterization as drivers of response/resistance. Analysis of RNA profiles showed that expression of immune response-related genes was enriched in tumors from patients with complete response, while expression of keratinization-related genes was enriched in tumors from patients who experienced rapid progression.

Conclusions: These findings suggest that enriched immune infiltration might be a shared feature favoring response to both targeted and immune therapies, while features of innate resistance to targeted and immune therapies were distinct.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083896PMC
June 2019

Immunomodulatory Properties of DNA Hypomethylating Agents: Selecting the Optimal Epigenetic Partner for Cancer Immunotherapy.

Front Pharmacol 2018 7;9:1443. Epub 2018 Dec 7.

Department of Oncology, Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy.

DNA hypomethylating agents (DHAs) play a well-acknowledged role in potentiating the immunogenicity and the immune recognition of neoplastic cells. This immunomodulatory activity of DHAs is linked to their ability to induce or to up-regulate on neoplastic cells the expression of a variety of immune molecules that play a crucial role in host-tumor immune interactions. To further investigate the clinical potential of diverse epigenetic compounds when combined with immunotherapeutic strategies, we have now compared the tumor immunomodulatory properties of the first generation DHAs, azacytidine (AZA) and decitabine (DAC) and of the next generation DHA, guadecitabine. To this end, human melanoma and hematological cancer cells were treated with 1 μM guadecitabine, DAC or AZA and then studied by molecular and flow cytometry analyses for changes in their baseline expression of selected immune molecules involved in different mechanism(s) of immune recognition. Results demonstrated a stronger DNA hypomethylating activity of guadecitabine and DAC, compared to AZA that associated with stronger immunomodulatory activities. Indeed, the mRNA expression of cancer testis antigens, immune-checkpoint blocking molecules, immunostimulatory cytokines, involved in NK and T cell signaling and recruiting, and of genes involved in interferon pathway was higher after guadecitabine and DAC compared to AZA treatment. Moreover, a stronger up-regulation of the constitutive expression of HLA class I antigens and of Intercellular Adhesion Molecule-1 was observed with guadecitabine and DAC compared to AZA. Guadecitabine and DAC seem to represent the optimal combination partners to improve the therapeutic efficacy of immunotherapeutic agents in combination/sequencing clinical studies.
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http://dx.doi.org/10.3389/fphar.2018.01443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293200PMC
December 2018

Addressing current challenges and future directions in immuno-oncology: expert perspectives from the 2017 NIBIT Foundation Think Tank, Siena, Italy.

Cancer Immunol Immunother 2019 Jan 18;68(1):1-9. Epub 2018 Dec 18.

Parker Institute for Cancer Immunotherapy, 1 Letterman Drive, San Francisco, CA, 94129, USA.

A collaborative think tank involving panellists from immuno-oncology networks, clinical/translational investigators and the pharmaceutical industry was held in Siena, Italy, in October 2017 to discuss the evolving immune-oncology landscape, identify selected key challenges, and provide a perspective on the next steps required in the translation of current research and knowledge to clinical reality. While there is a trend of combining new agents (e.g., co-stimulator agonists) with a PD-1/PD-L1 treatment backbone, use of alternative combination therapy approaches should also be considered. While the rapid evolution in systems biology provides a deeper understanding of tumor and tumor microenvironment heterogeneity, there remains the need to identify and define genuinely predictive biomarkers to guide treatment and patient selection. Cross-specialty and cross-sector collaboration, along with a broader collective data-sharing approach are key to optimizing immuno-oncology therapy in clinical practice. Continued support of younger research-clinicians is essential for future success in clinical, translational and basic science investigations.
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http://dx.doi.org/10.1007/s00262-018-2285-yDOI Listing
January 2019

The Italian Network for Tumor Bio-Immunotherapy (NIBIT) Foundation: ongoing and prospective activities in immuno-oncology.

Cancer Immunol Immunother 2019 Jan 18;68(1):143-150. Epub 2018 Dec 18.

Center for Immuno-Oncology, Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Viale Mario Bracci, 16, 53100, Siena, Italy.

The ongoing revolution in cancer immunotherapy stems from the knowledge that distinct immune-checkpoints regulate the physiological crosstalk between and among immune cells by delivering inhibitory or activating signals. These notions, and the availability of mAb directed to diverse immune-checkpoint molecules, have led to a significant clinical improvement in cancer treatment. In this scenario, further achievements are undoubtedly to be expected from the contribution of novel, proof-of-principle clinical trials designed to explore the therapeutic efficacy of new immunotherapy-based combinations and treatment sequences. Along these lines, the clinical translation of pre-clinical evidence generated by non-profit research entities is likely to provide a significant contribution to gaining new insights that will further boost the field of cancer immunotherapy. To pursue this goal, and to provide comprehensive educational programs in immune-oncology (I-O), several national and global networks have been revitalized or newly established in recent years. This rapidly evolving scenario led the Board of Directors of the Italian Network of Tumor Bio-Immunotherapy (NIBIT) to establish the NIBIT Foundation. This Focused Research Review summarizes the main ongoing and prospective I-O activities of the NIBIT Foundation.
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http://dx.doi.org/10.1007/s00262-018-2286-xDOI Listing
January 2019

Collapse of the Plasmacytoid Dendritic Cell Compartment in Advanced Cutaneous Melanomas by Components of the Tumor Cell Secretome.

Cancer Immunol Res 2019 01 6;7(1):12-28. Epub 2018 Nov 6.

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.

Melanoma is an immunogenic neoplasm infiltrated by T cells, although these adaptive T cells usually fail to eradicate the tumor. Plasmacytoid dendritic cells (PDCs) are potent regulators of the adaptive immune response and can eliminate melanoma cells via TLR-mediated effector functions. The PDC compartment is maintained by progressively restricted bone marrow progenitors. Terminally differentiated PDCs exit the bone marrow into the circulation, then home to lymph nodes and inflamed peripheral tissues. Infiltration by PDCs is documented in various cancers. However, their role within the melanoma immune contexture is not completely known. We found that in locoregional primary cutaneous melanoma (PCM), PDC infiltration was heterogeneous, occurred early, and was recurrently localized at the invasive margin, the site where PDCs interact with CD8 T cells. A reduced PDC density was coupled with an increased Breslow thickness and somatic mutations at the p.Q61 codon. Compared with what was seen in PCM, high numbers of PDCs were found in regional lymph nodes, as also identified by analysis. In contrast, in metastatic melanoma patients, PDCs were mostly absent in the tumor tissues and were significantly reduced in the circulation, particularly in the advanced M1c group. Exposure of circulating PDCs to melanoma cell supernatant (SN-mel) depleted of extracellular vesicles resulted in significant PDC death. SN-mel exposure also resulted in a defect of PDC differentiation from CD34 progenitors. These findings indicate that soluble components released by melanoma cells support the collapse of the PDC compartment, with clinical implications for refining TLR agonist-based trials.
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http://dx.doi.org/10.1158/2326-6066.CIR-18-0141DOI Listing
January 2019

Long-term follow up of metastatic melanoma patients treated with Thymosin alpha-1: investigating immune checkpoints synergy.

Expert Opin Biol Ther 2018 07;18(sup1):77-83

a Medical Oncology and Immunotherapy, Center for Immuno-Oncology , University Hospital of Siena , Siena , Italy.

Background: Immune checkpoint blockade antibodies (imAbs), such as the anti Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) ipilimumab (IPI) raised overall survival (OS) in metastatic melanoma (MM). Further, long-term OS is a crucial endpoint in MM. Thymosin alpha-1 (Tα1) with dacarbazine (DTIC) showed activity in a phase II trial and a compassionate use program (EAP). We report on long-term follow-up of patients treated with Tα1 to investigate the preconditioning role of Tα1 in imAbs-treated patients.

Methods: Records of patients with melanoma treated with Tα1 within a phase II trial and EAP program were reviewed comparing median OS among patients that sequentially received anti-CTLA-4 imAb and Tα1. Further, the effect of Tα1 on IPI long-term survivor patients was investigated.

Results: Among patients treated with Tα1, 21/61 patients received sequentially even anti CTLA-4 imAbs. Median OS at the data cut-off was 57.8 and 7.4 months in patients treated sequentially with anti-CTLA-4 imAbs or not, respectively. Moreover, pretreatment with Tα1 in all (95) IPI-evaluable patients confirmed a significant increase in long-term OS.

Conclusion: This is the first report on long-term follow-up of Tα1-treated patients. Moreover, an advantage in OS in patients sequentially treated with Tα1 and IPI was seen that suggests a synergistic effect.
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http://dx.doi.org/10.1080/14712598.2018.1494717DOI Listing
July 2018