@article{PagottoSimeoneBroccoetal.2023, author = {Pagotto, Sara and Simeone, Pasquale and Brocco, Davide and Catitti, Giulia and De Bellis, Domenico and Vespa, Simone and Di Pietro, Natalia and Marinelli, Lisa and Di Stefano, Antonio and Veschi, Serena and De Lellis, Laura and Verginelli, Fabio and Kaitsas, Francesco and Iezzi, Manuela and Pandolfi, Assunta and Visone, Rosa and Tinari, Nicola and Caruana, Ignazio and Di Ianni, Mauro and Cama, Alessandro and Lanuti, Paola and Florio, Rosalba}, title = {CAR-T-derived extracellular vesicles: a promising development of CAR-T anti-tumor therapy}, series = {Cancers}, volume = {15}, journal = {Cancers}, number = {4}, issn = {2072-6694}, doi = {10.3390/cancers15041052}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304195}, year = {2023}, abstract = {Extracellular vesicles (EVs) are a heterogenous population of plasma membrane-surrounded particles that are released in the extracellular milieu by almost all types of living cells. EVs are key players in intercellular crosstalk, both locally and systemically, given that they deliver their cargoes (consisting of proteins, lipids, mRNAs, miRNAs, and DNA fragments) to target cells, crossing biological barriers. Those mechanisms further trigger a wide range of biological responses. Interestingly, EV phenotypes and cargoes and, therefore, their functions, stem from their specific parental cells. For these reasons, EVs have been proposed as promising candidates for EV-based, cell-free therapies. One of the new frontiers of cell-based immunotherapy for the fight against refractory neoplastic diseases is represented by genetically engineered chimeric antigen receptor T (CAR-T) lymphocytes, which in recent years have demonstrated their effectiveness by reaching commercialization and clinical application for some neoplastic diseases. CAR-T-derived EVs represent a recent promising development of CAR-T immunotherapy approaches. This crosscutting innovative strategy is designed to exploit the advantages of genetically engineered cell-based immunotherapy together with those of cell-free EVs, which in principle might be safer and more efficient in crossing biological and tumor-associated barriers. In this review, we underlined the potential of CAR-T-derived EVs as therapeutic agents in tumors.}, language = {en} } @article{SchwinnMokhtariThuseketal.2021, author = {Schwinn, Stefanie and Mokhtari, Zeinab and Thusek, Sina and Schneider, Theresa and Sir{\´e}n, Anna-Leena and Tiemeyer, Nicola and Caruana, Ignazio and Miele, Evelina and Schlegel, Paul G. and Beilhack, Andreas and W{\"o}lfl, Matthias}, title = {Cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-021-93586-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261476}, year = {2021}, abstract = {Medulloblastoma is the most common high-grade brain tumor in childhood. Medulloblastomas with c-myc amplification, classified as group 3, are the most aggressive among the four disease subtypes resulting in a 5-year overall survival of just above 50\%. Despite current intensive therapy regimens, patients suffering from group 3 medulloblastoma urgently require new therapeutic options. Using a recently established c-myc amplified human medulloblastoma cell line, we performed an in-vitro-drug screen with single and combinatorial drugs that are either already clinically approved or agents in the advanced stage of clinical development. Candidate drugs were identified in vitro and then evaluated in vivo. Tumor growth was closely monitored by BLI. Vessel development was assessed by 3D light-sheet-fluorescence-microscopy. We identified the combination of gemcitabine and axitinib to be highly cytotoxic, requiring only low picomolar concentrations when used in combination. In the orthotopic model, gemcitabine and axitinib showed efficacy in terms of tumor control and survival. In both models, gemcitabine and axitinib were better tolerated than the standard regimen comprising of cisplatin and etoposide phosphate. 3D light-sheet-fluorescence-microscopy of intact tumors revealed thinning and rarefication of tumor vessels, providing one explanation for reduced tumor growth. Thus, the combination of the two drugs gemcitabine and axitinib has favorable effects on preventing tumor progression in an orthotopic group 3 medulloblastoma xenograft model while exhibiting a favorable toxicity profile. The combination merits further exploration as a new approach to treat high-risk group 3 medulloblastoma.}, language = {en} } @article{PellegrinoDelBufaloDeAngelisetal.2020, author = {Pellegrino, Marsha and Del Bufalo, Francesca and De Angelis, Biagio and Quintarelli, Concetta and Caruana, Ignazio and de Billy, Emmanuel}, title = {Manipulating the metabolism to improve the efficacy of CAR T-cell immunotherapy}, series = {Cells}, volume = {10}, journal = {Cells}, number = {1}, issn = {2073-4409}, doi = {10.3390/cells10010014}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220140}, year = {2020}, abstract = {The adoptive transfer of the chimeric antigen receptor (CAR) expressing T-cells has produced unprecedented successful results in the treatment of B-cell malignancies. However, the use of this technology in other malignancies remains less effective. In the setting of solid neoplasms, CAR T-cell metabolic fitness needs to be optimal to reach the tumor and execute their cytolytic function in an environment often hostile. It is now well established that both tumor and T cell metabolisms play critical roles in controlling the immune response by conditioning the tumor microenvironment and the fate and activity of the T cells. In this review, after a brief description of the tumoral and T cell metabolic reprogramming, we summarize the latest advances and new strategies that have been developed to improve the metabolic fitness and efficacy of CAR T-cell products.}, language = {en} } @article{PelosiFioreDiMatteoetal.2021, author = {Pelosi, Andrea and Fiore, Piera Filomena and Di Matteo, Sabina and Veneziani, Irene and Caruana, Ignazio and Ebert, Stefan and Munari, Enrico and Moretta, Lorenzo and Maggi, Enrico and Azzarone, Bruno}, title = {Pediatric tumors-mediated inhibitory effect on NK cells: the case of neuroblastoma and Wilms' tumors}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {10}, issn = {2072-6694}, doi = {10.3390/cancers13102374}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239615}, year = {2021}, abstract = {Natural killer (NK) cells play a key role in the control of cancer development, progression and metastatic dissemination. However, tumor cells develop an array of strategies capable of impairing the activation and function of the immune system, including NK cells. In this context, a major event is represented by the establishment of an immunosuppressive tumor microenvironment (TME) composed of stromal cells, myeloid-derived suppressor cells, tumor-associated macrophages, regulatory T cells and cancer cells themselves. The different immunoregulatory cells infiltrating the TME, through the release of several immunosuppressive molecules or by cell-to-cell interactions, cause an impairment of the recruitment of NK cells and other lymphocytes with effector functions. The different mechanisms by which stromal and tumor cells impair NK cell function have been particularly explored in adult solid tumors and, in less depth, investigated and discussed in a pediatric setting. In this review, we will compare pediatric and adult solid malignancies concerning the respective mechanisms of NK cell inhibition, highlighting novel key data in neuroblastoma and Wilms' tumor, two of the most frequent pediatric extracranial solid tumors. Indeed, both tumors are characterized by the presence of stromal cells acting through the release of immunosuppressive molecules. In addition, specific tumor cell subsets inhibit NK cell cytotoxic function by cell-to-cell contact mechanisms likely controlled by the transcriptional coactivator TAZ. These findings could lead to a more performant diagnostic approach and to the development of novel immunotherapeutic strategies targeting the identified cellular and molecular targets.}, language = {en} } @article{FioreVaccaTuminoetal.2021, author = {Fiore, Piera Filomena and Vacca, Paola and Tumino, Nicola and Besi, Francesca and Pelosi, Andrea and Munari, Enrico and Marconi, Marcella and Caruana, Ignazio and Pistoia, Vito and Moretta, Lorenzo and Azzarone, Bruno}, title = {Wilms' tumor primary cells display potent immunoregulatory properties on NK cells and macrophages}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {2}, issn = {2072-6694}, doi = {10.3390/cancers13020224}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222981}, year = {2021}, abstract = {The immune response plays a crucial defensive role in cancer growth and metastasis and is a promising target in different tumors. The role of the immune system in Wilm's Tumor (WT), a common pediatric renal malignancy, is still to be explored. The characterization of the immune environment in WT could allow the identification of new therapeutic strategies for targeting possible inhibitory mechanisms and/or lowering toxicity of the current treatments. In this study, we stabilized four WT primary cultures expressing either a blastematous (CD56\(^+\)/CD133\(^-\)) or an epithelial (CD56\(^-\)/CD133\(^+\)) phenotype and investigated their interactions with innate immune cells, namely NK cells and monocytes. We show that cytokine-activated NK cells efficiently kill WT cells. However, after co-culture with WT primary cells, NK cells displayed an impaired cytotoxic activity, decreased production of IFNγ and expression of CD107a, DNAM-1 and NKp30. Analysis of the effects of the interaction between WT cells and monocytes revealed their polarization towards alternatively activated macrophages (M2) that, in turn, further impaired NK cell functions. In conclusion, we show that both WT blastematous and epithelial components may contribute directly and indirectly to a tumor immunosuppressive microenvironment that is likely to play a role in tumor progression.}, language = {en} }