MARCO TEÓRICO
2. Necesidad de una propuesta integral
PROGRAM HIGHLIGHTS
The recent success of novel cancer therapeutics based on immunomodulation has finally shown the key role of the immune system in controlling tumor growth. Evidence is also emerging regarding the influence that immunity exerts on disease progression and on the response to cancer treatment including targeted therapies. Hence, the study of immune-tumor interactions aimed at characterizing the “immune profile” at the single patient level represents a promising tool for the identification of novel predicting/prognostic factors and new therapeutic targets. Thanks to our long-standing experience in tumor immunology, continuously updated at the scientific and technological levels through collaboration with several national and international groups and networks, we are collecting a broad and comprehensive picture of immune-cancer cross-talk and its outcome in patients. Immunomonitoring is performed according to standardized protocols and SOPs, including sample collection and immunological testing. The active and productive collaboration with several clinical units allows the design of studies that meet specific and relevant clinical needs as well as timely patient selection and accrual. Based on these features, we are dissecting the mechanisms of cancer-mediated immunosuppression, possibly finding common features and patterns across different tumor histologies. Focusing on patients and defined questions, we are committed to verify whether investigating the immune system can provide relevant information about patient prognosis and response to treatment. Understanding the pathways regulating tumor immunity may also contribute to the identification of novel therapeutic strategies for cancer patients.
PROGRAM MEMBERSHIP
Unit of Immunotherapy of Human Tumors
Study design and management, immunological and genetic analyses, data interpretation.
Melanoma Unit
Patient selection, collaboration in study design.
Liver Unit
Collaboration in study design, patient selection, result discussion and data interpretation.
Sarcoma Unit
Patient selection, collaboration in study design.
Head and Neck Oncology
Patient selection, collaboration in study design, result discussion and data interpretation.
Unit of Functional Genomics
Genetic profiling, data analysis
MIA consortium
Imaging studies
Unit of Statistics and Epidemiology
Collaboration in study design, data analysis SELECTED RECENT PUBLICATIONS
Camisaschi C., Filipazzi P., Tazzari M., Casati C., Beretta V., Pilla L., Patuzzo R., Maurichi A., Cova A., Maio M., Chiarion-Sileni V., Tragni G., Santinami M., Vergani B., Villa A., Berti E., Umansky L., Beckhove P., Umansky V., Parmiani G., Rivoltini L., Castelli C.: Effects of cyclophosphamide and IL-2 on regulatory CD4+ T cell frequency and function in melanoma patients vaccinated with HLA-class I peptides: impact on the antigen-specific T cell response. Cancer Immunol Immunother 2013; 62(5): 897-908
Castelli C., Tazzari M., Negri T., Vergani B., Rivoltini L., Stacchiotti S., Pilotti S.: Structured myeloid cells and anti-angiogenic therapy in alveolar soft part sarcoma. J Transl Med 2013; 11:237
Filipazzi P., Pilla L., Mariani L., Patuzzo R., Castelli C., Camisaschi C., Maurichi A., Cova A., Rigamonti G., Giardino F., Di Florio A., Asioli M., Frati P., Sovena G., Squarcina P., Maio M., Danielli R., Chiarion-Sileni V., Villa A., Lombardo C., Tragni G., Santinami M., Parmiani G., Rivoltini L.: Limited induction of tumor cross-reactive T cells without a measurable clinical benefit in early melanoma patients vaccinated with human leukocyte antigen class I-modified peptides. Clin Cancer Res 2012; 18(23): 6485-6496
Calcinotto A., Filipazzi P., Grioni M., Iero M., De Milito A., Ricupito A., Cova A., Canese R., Jachetti E., Rossetti M., Huber V., Parmiani G., Generoso L., Santinami M., Borghi M., Fais S., Bellone M., Rivoltini L.: Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res 2012; 72(11): 2746-2756
ASSOCIATED CLINICAL TRIALS
Experimental Clinical Study no Profit
AdESOM: Effetto immunomodulatorio e antitumorale dell’ esomeprazolo ad alte dosi in regime neoadiuvante e adiuvante in pazienti con melanoma in stadio III. Studio pilota randomizzato trattamento vs controllo
PROVAX: Studio di vaccinazione, in aperto, di fase II con peptidi di survivina emulsionati in Montanide® ISA 51VG dopo somministrazione di IMP321TM, in pazienti con carcinoma prostatico in recidiva biochimica
MULTIMELMARKERS: Identificazione di marcatori molecolari del melanoma multiplo
NIBIT-001: A Phase II Study of the Combination of Ipilimumab and Fotemustine in Patients with Unresectable Locally Advanced or Metastatic Malignant Melanoma
Experimental Clinical Study Profit
GINGER: Studio multicentrico, randomizzato, in doppio cieco, controllato verso placebo per valutare l’attività di un integratore alimentare a base di Ginger (Zingiber officinalis) nella gestione della nausea in pazienti che ricevono trattamenti altamente emetizzanti e la terapia antiemetica standard
7. Acidity is a powerful tool for tumor microenviroment to anergize immune responses in melanoma. A clinical trial investigating the ability of anti-acid drugs to improve tumor immunity and control tumor growth is ongoing in melanoma patients. Altogether, these data strongly confirm the potentiality of immune-related pathways as novel source of biomarkers for patient selection and management in cancer
METRIC/MEK114267: Studio di Fase III randomizzato, in aperto, per confrontare GSK1120212 verso chemioterapia in soggetti con melanoma avanzato o metastatico positivo alle mutazioni di BRAF V600E/K
NYESO-1: An open Phase I study of immunization with the recNY ESO 1 + AS15 Antigen-Specific Cancer Immunotherapeutic in patients with NY-ESO-1 positive unresectable and progressive metastatic cutaneous melanoma
PRAME: An open, dose-escalation Phase I/II study to assess the safety, immunogenicity and clinical activity of recPRAME + AS15 Antigen- Specific Cancer Immunotherapeutic as first-line treatment of patients with PRAME-positive metastatic melanoma
Observational Clinical Studies (Non-profit)
EPApHIL-6: Analisi dell’infiltrato infiammatorio come fattore prognostico e target terapeutico in pazienti con carcinoma epatico. Ruolo della componente mieloide e dei pathway coinvolti nella regolazione del pH
miRNA: Identificazione di microRNA circolanti quali potenziali indicatori di progressione nel melanoma metastatico
BRAF-MEK: Studio dell’effetto immunomodulatorio degli inibitori di BRAF e MEK in pazienti con melanoma
Target Therapy: Valutazione del ruolo dei meccanismi
immunosoppressivi nella prognosi e nella risposta al trattamento con farmaci ‘targeted therapy’ in pazienti affetti da sarcoma
SELECTED RECENT MAJOR GRANTS
Project MCO-9998 Special Program Molecular Clinical Oncology, AIRC 5 per Mille “Cell therapy with TRAIL-armed, genetically engineered or phenotypically redirected, effectors”
Duration: 01/07/2010 - 30/06/2015
Project n. 12162 - AIRC 5 per Mille “Tumor-Microenvironment related changes as new tools for early detection and assessment of high-risk disease”
Duration: 31/12/2011 - 30/12/2016
Project AIRC IG-14285 “Modulation of melanoma immunosuppressive microenvironment by proton pump inhibitors”.
Duration: 02/01/2014 - 01/01/2015
Project AIRC IG-13335 “From regional node to systemic immunity suppression in melanoma metastatic progression”
Duration: 02.01.2014 - 01.01.2015
MINISTERO della SALUTE convenzione n. 52/RF-2010-2312620 “IL-6-related inflammation signatures as a predictive marker of recurrence in liver cancer patients”
Duration: 03/12/2012 - 02/12/2015
Harry J Lloyd Charitable Trust “Study of microRNA related to myeloid derived suppressor cells in early melanoma patients” Duration: 14/06/2013 - 30/06/2015
KEYWORDS
Immune suppression, myeloid-derived suppressor cells, exosomes, miRNA
Figure: Immunosuppressive and exhausted lymphocytes in metastatic sentinel node from melanoma patients with unfavorable disease course at 5
years follow-up. Double staining for CD30 and CD147, Foxp3, and PD1 in a representative PP sample showing cells expressing one or both markers (magnification, ×100). Confocal images of sections stained for CD30 in green and for CD147 or PD1 in red are shown (merge). In the CD30-Foxp3 double staining, CD30+ cells are indicated by red, and nuclear staining for Foxp3 is indicated by brown. From Vallacchi V et al. Cancer Res 2014;74:130-140