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Localization of chemotherapy at the tumor site can improve therapeutic efficacy and reduce systemic toxicity. In previous studies we have shown that mesenchymal stromal cells (MSCs) isolated from bone marrow or fat tissue, can be loaded with the anti-cancer drug Paclitaxel (PTX) and kill cancer cells when localized nearby. We here investigated the capacity of human micro-fragmented adipose tissue (MFAT), used as a natural container of MSCs, to delivery PTX with the idea to improve local drug concentration and to prolong the therapeutic activity. Surprisingly, we found that both fresh but also devitalized MFAT (DMFAT) (by freezing/thawing procedure) were very effective biomaterials able to deliver and release significant amount of PTX, killing several human cancer cell lines in vitro with an impressive long lasting activity. In an orthotopic mice model of Neuroblastoma (NB) transplant, we found that DMFAT loaded with PTX prevents or delay NB relapse when placed in the surgical area of tumor resection, without any collateral toxicity. We concluded that MFAT, but also DMFAT, may work as natural biomaterials that can be used to localize and release anti-cancer molecules at the tumor site. In addition, the procedure to easily prepare DMFAT did not alter its natural scaffold structure. This suggest that such biomaterial may have a prominent role in the near future in many oncological applications to delivery anti-cancer drugs, helping to fight cancer in human. Citation Format: Giulio Alessandri, Valentina Coccè, Fabio Pastorino, Rita Paroni, Michele Deicas, Francesco Restelli, Carlo Tremolada, Angiola Berenzi, Eugenio Parati, Anna Teresa Brini, Giampietro Bondiolotti, Augusto Pessina, Mirco Ponzoni. Microfragmented human fat tissue is a natural scaffold for drug delivery: potential application in cancer chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2160.

Hepatocellular carcinoma (HCC) is one of most malignant and aggressive human tumors. Transforming growth factor-β1 (TGF-β1) and its coreceptor CD105 have been shown to contribute to HCC malignant progression. TGF-β1 and CD105 have also been implicated in angiogenesis, but their role in the vascularization of HCC has not been investigated. To fill this gap, we studied the effect of TGF-β1 and CD105 on HCC-derived endothelium. By using immunomagnetic beads, we isolated and cultured endothelial cells (ECs) from HCC (HCC-EC) and adjacent nonneoplastic tissue (nNL-ECs) obtained from 24 liver biopsies. HCC and nNL biopsies were also analyzed by immunohistochemistry for the expression of CD105, TGF-β1, Ve-cadherin (Ve-cad), CD44, β-catenin, and E-cadherin. Compared with nNL-ECs, HCC-ECs had higher expression of CD105, enhanced spontaneous motility, and greater capacity to migrate in response to TGF-β1 (5 ng/mL), particularly in the presence of a fibronectin matrix. The chemotactic effect of TGF-β1 was blocked by anti-CD105 antibodies and correlated with the grade of HCC malignancy. Histologic examination of HCC biopsies showed that HCCs with the worse malignant features had the highest expression of TGF-β1, CD105, and angiogenic markers (Ve-cad and CD44). Because CD105 was highly expressed in microvessels at the tumor periphery and TGF-β1 staining was only found in neoplastic hepatocytes, we conclude that HCC-derived TGF-β1 may act as a chemoattractant for CD105-expressing ECs and as a promoter of tumor angiogenesis. Thus, drugs that selectively target the TGF-β1/CD105 axis may interfere with HCC-related angiogenesis and HCC progression. [Cancer Res 2008;68(20):8626–34]

Mesenchymal stromal cells (MSCs) are considered an important therapeutic tool in cancer therapy. Because MSCs may home tumor microenvironment they have the possibility to directly delivery molecules to cancer cells. We have demonstrated that MSCs, upon in vitro priming with anti-cancer drug, become drug-releasing mesenchymal cells (Dr-MCs) able to strongly inhibit cancer cells growth. In order to expand our studies we here investigated whether intravenous (i.v) injection of MSCs loaded with Paclitaxel (PTX) were able to reduce B16 melanoma lung metastasis formation. To this end, as Dr-MCs, the murine MSC line SR4987 was used. SR4987 cells were loaded with PTX (SR4987PTX) by incubating for 24h with 2000ng/ml PTX. The anti-metastatic activity of SR4987PTX was evaluated in mice injected i.v. with 2.5 × 105 B16 melanoma cells. Tracking of the SR4987 in the lung was studied by immunohistochemistry using anti-Sca-1 antibodies. Adhesion and migration experiments were performed to elucidated the mechanism of SR4987PTX homing. In summary, we found that three i.v. injections of SR4987PTX on day 5, 10 and 15 after tumor injection almost completely (>90% inhibition) abolished B16 lung metastasis. This effect was significantly superior (p Citation Format: Giulio Alessandri, Carlo Leonetti, Simona Artuso, Augusto Orlandi, Daniela Passeri, Anna Benetti, Angiola Berenzi, Enrico Dessy, Luisa Pascucci, Piero Ceccarelli, Arianna Bonomi, Valentina Coccè, Nazario Portolani, Valentina Ceserani, Eugenio Parati, Augusto Pessina. Drug-releasing mesenchymal cells strongly suppress B16 lung metastasis in a syngeneic murine model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4237. doi:10.1158/1538-7445.AM2015-4237

Recurrent glioblastoma (GB) are highly aggressive tumors allowing 6-8 month survival. Here we evaluated the possible benefits of immunotherapy with mature dendritic cells (DC) loaded with autologous tumor lysate in 15 patients with recurrent GB. After a median follow-up of 8 months median progression free survival (PFS) was 4.4 months and median overall survival (OS) 8.0 months. Patients with small tumors at first vaccination (< 20 cc; n = 8) had significantly longer PFS and OS than others: 6.0 vs 3.0 months (p = 0.01) and 16.5 vs 7.0 months (p = 0.003), respectively. Patients were analysed for CD8+ T cells, CD56+ NK cells and other relevant immunological parameters in peripheral blood before and after immunization, defining a vaccination/baseline ratio (V/B ratio). Increased V/B ratio of NK but not CD8+ T cells was significantly associated to longer PFS and OS. Patients showing NK cell responses had higher levels of IFN-γ and E4BP4, the NK cell transcription factor. Furthermore, NK V/B ratio was inversely correlated with TGF-β2 and VEGF V/B ratio. The results suggest that tumor-loaded DC may increase survival of recurrent GB after effective tumor debulking and emphasize the role of NK cell responses in this therapeutic setting. Citation Format: Serena Pellegatta, Marica Eoli, Simona Frigerio, Carlo Antozzi, Maria Grazia Bruzzone, Gabriele Cantini, Sara Nava, Elena Anghileri, Lucia Cuppini, Valeria Cuccarini, Emilio Ciusani, Marta Dossena, Bianca Pollo, Renato Mantegazza, Eugenio A. Parati, Gaetano Finocchiaro. NK cell response and tumor debulking are associated to prolonged survival in recurrent glioblastoma treated by dendritic cells loaded with autologous tumor lysate. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2839. doi:10.1158/1538-7445.AM2013-2839 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Background: Mesenchymal stem cells (MSCs) may represent an ideal candidate to deliver anti-cancer drugs. In a previous study, we demonstrated that simple exposure of bone marrow (BM) derived MSCs to high doses of Doxorubicin, led them to acquire anti-proliferative potential towards co-cultured haematopoitic stem cells (HSCs). We thus hypothesized whether MSCs, once primed in vitro with anti-cancer drugs and then localized near cancer cells, can inhibit proliferation. Methods: Paclitaxel (PTX) was used to prime culture of mouse and human MSCs. Incorporation of PTX into MSCs (MSCsPTX) was studied by using FICT-labelled-PTX and analyzed by FACS and confocal microscopy. Release of PTX in culture medium by MSCsPTX was investigated by HPLC. Culture of Endothelial cells (ECs) and aorta ring assay were used to test the anti-angiogenic activity of MSCsPTX, while anti-tumor activity was tested in vitro on the proliferation of different tumor cell lines and in vivo by co-transplanting MSCsPTX with cancer cells in mice. Results: MSCs were able to rapidly incorporate PTX and could slowly release PTX in the culture medium in a time dependent manner. Primed MSCsPTX acquired a potent anti-tumor and anti-angiogenic activity in vitro that was dose dependent, and demonstrable by using their conditioned medium or by co-culture assay. Finally, MSCsPTX co-injected in immunodeficient mice with DU145 and B16 cancer cells, significantly delayed tumor takes and reduced tumor growth. Conclusions: These data demonstrate that, without any genetic manipulation, MSCs can uptake and subsequently slowly release PTX, becoming a potential new tool for cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4354. doi:10.1158/1538-7445.AM2011-4354