-
1دورية أكاديمية
المؤلفون: Feng, Zipei, Puri, Sachin, Moudgil, Tarsem, Wood, William, Hoyt, Clifford, Wang, Chichung, Urba, Walter, Curti, Brendan, Bifulco, Carlo, Fox, Bernard
مصطلحات موضوعية: Tumor-infiltrating lymphocytes (TIL), multispectral imaging, Adoptive T cell therapy (ACT), Immunotherapy, Melanoma, Immunoprofiling, Immunoscore, Immunotherapy biomarker
الوصف: Background Adoptive T cell therapy (ACT) has shown great promise in melanoma, with over 50 % response rate in patients where autologous tumor-reactive tumor-infiltrating lymphocytes (TIL) can be cultured and expanded. A major limitation of ACT is the inability to generate or expand autologous tumor-reactive TIL in 25–45 % of patients tested. Methods that successfully identify tumors that are not suitable for TIL generation by standard methods would eliminate the costs of fruitless expansion and enable these patients to receive alternate therapy immediately. Methods Multispectral fluorescent immunohistochemistry with a panel including CD3, CD8, FoxP3, CD163, PD-L1 was used to analyze the tumor microenvironment in 17 patients with melanoma among our 36-patient cohort to predict successful TIL generation. Additionally, we compared tumor fragments and enzymatic digestion of tumor samples for efficiency in generating tumor-reactive TIL. Results Tumor-reactive TIL were generated from 21/36 (58 %) of melanomas and for 12/13 (92 %) tumors where both enzymatic and fragment methods were compared. TIL generation was successful in 10/13 enzymatic preparations and in 10/13 fragment cultures; combination of both methods resulted in successful generation of autologous tumor-reactive TIL in 12/13 patients. In 17 patients for whom tissue blocks were available, IHC analysis identified that while the presence of CD8 + T cells alone was insufficient to predict successful TIL generation, the CD8 + to FoxP3 + ratio was predictive with a positive-predictive value (PPV) of 91 % and negative-predictive value (NPV) of 86 %. Incorporation of CD163+ macrophage numbers and CD8:PD-L1 ratio did not improve the PPV. However, the NPV could be improved to 100 % by including the ratio of CD8 + :PD-L1 + expressing cells. Conclusion This is the first study to apply 7-color multispectral immunohistochemistry to analyze the immune environment of tumors from patients with melanoma. Assessment of the data using unsupervised hierarchical ...
-
2تقرير
المؤلفون: Ascierto, Paolo, Agarwala, Sanjiv, Botti, Gerardo, Cesano, Alessandra, Ciliberto, Gennaro, Davies, Michael, Demaria, Sandra, Dummer, Reinhard, Eggermont, Alexander, Ferrone, Soldano, Fu, Yang, Gajewski, Thomas, Garbe, Claus, Huber, Veronica, Khleif, Samir, Krauthammer, Michael, Lo, Roger, Masucci, Giuseppe, Palmieri, Giuseppe, Postow, Michael, Puzanov, Igor, Silk, Ann, Spranger, Stefani, Stroncek, David, Tarhini, Ahmad, Taube, Janis, Testori, Alessandro, Wang, Ena, Wargo, Jennifer, Yee, Cassian, Zarour, Hassane, Zitvogel, Laurence, Fox, Bernard, Mozzillo, Nicola, Marincola, Francesco, Thurin, Magdalena
الوصف: The sixth “Melanoma Bridge Meeting” took place in Naples, Italy, December 1st–4th, 2015. The four sessions at this meeting were focused on: (1) molecular and immune advances; (2) combination therapies; (3) news in immunotherapy; and 4) tumor microenvironment and biomarkers. Recent advances in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS) of cancer patients. Immunotherapies in particular have emerged as highly successful approaches to treat patients with cancer including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin’s disease. Specifically, many clinical successes have been using checkpoint receptor blockade, including T cell inhibitory receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death-1 (PD-1) and its ligand PD-L1. Despite demonstrated successes, responses to immunotherapy interventions occur only in a minority of patients. Attempts are being made to improve responses to immunotherapy by developing biomarkers. Optimizing biomarkers for immunotherapy could help properly select patients for treatment and help to monitor response, progression and resistance that are critical challenges for the immuno-oncology (IO) field. Importantly, biomarkers could help to design rational combination therapies. In addition, biomarkers may help to define mechanism of action of different agents, dose selection and to sequence drug combinations. However, biomarkers and assays development to guide cancer immunotherapy is highly challenging for several reasons: (i) .
-
3تقرير
المؤلفون: Yuan, Jianda, Wang, Ena, Fox, Bernard
مصطلحات موضوعية: Immune monitoring, Protein microarray, Biomarker, Seromics, Autoantibody response
-
4تقرير
المؤلفون: Ascierto, Paolo, Ascierto, Maria, Formenti, Silvia, Gnjatic, Sacha, Hammers, Hans, Hirsh, Vera, Kiessling, Rolf, Melero, Ignacio, Nanda, Rita, Pawelec, Graham, Pignata, Sandro, Romero, Pedro, Speiser, Daniel, Fox, Bernard, Marincola, Francesco
الوصف: Harnessing the immune system and preventing immune escape, the immunotherapy of cancer provides great potential for clinical application, in broad patient populations, achieving both conventional and unconventional clinical responses. After the substantial advances in melanoma, the focus of cancer immunotherapy has expanded to include many other cancers. Targeting immune checkpoints and further mechanisms used by tumors to avoid anticancer immunity, different approaches are under evaluation, including combination therapies. The first Immunotherapy Bridge meeting focused on various cancer types including melanoma, non-small cell lung cancer, renal cell, breast and ovarian carcinoma, and discussed mechanisms of action of single agents and combination strategies, and the prediction of clinical responses.
-
5تقرير
المؤلفون: Ye, Wei, Xing, Yun, Paustian, Christopher, van de Ven, Rieneke, Moudgil, Tarsem, Hilton, Traci L, Fox, Bernard A, Urba, Walter J, Zhao, Wei, Hu, Hong-Ming
مصطلحات موضوعية: Autophagosome, Cross-presentation, Immunological monitoring, Immunotherapy biomarker, Viral vaccine, Cancer vaccine, Memory antigen-specific T cells, Proteasome
الوصف: Background Autophagy regulates innate and adaptive immune responses to pathogens and tumors. We have reported that autophagosomes derived from tumor cells after proteasome inhibition, DRibbles (Defective ribosomal products in blebs), were excellent sources of antigens for efficient cross priming of tumor-specific CD8 + T cells, which mediated regression of established tumors in mice. But the activity of DRibbles in human has not been reported. Methods DRibbles or cell lysates derived from HEK293T or UbiLT3 cell lines expressing cytomegalovirus (CMV) pp65 protein or transfected with a plasmid encoding dominant HLA-A2 restricted CMV, Epstein-Barr virus (EBV), and Influenza (Flu) epitopes (CEF) were loaded onto human monocytes or PBMCs and the response of human CMV pp65 or CEF antigen-specific CD4 + and CD8 + memory T cells was detected by intracellular staining. The effect of cytokines (GM-CSF, IL-4, IL-12, TNF-α, IFN-α and IFN-γ) TLR agonists (Lipopolysaccharide, Polyinosinic-polycytidylic acid (poly(I:C), M52-CpG, R848, TLR2 ligand) and CD40 ligand on the cross-presentation of antigens contained in DRibbles or cell lysates was explored. Results In this study we showed that purified monocytes, or human PBMCs, loaded with DRibbles isolated from cells expressing CMV or CEF epitopes, could activate CMV- or CEF-specific memory T cells. DRibbles were significantly more efficient at stimulating CD8 + memory T cells compared to cell lysates expressing the same antigenic epitopes. We optimized the conditions for T-cell activation and IFN-γ production following direct loading of DRibbles onto PBMCs. We found that the addition of Poly(I:C), CD40 ligand, and GM-CSF to the PBMCs together with DRibbles significantly increased the level of CD8 + T cell responses. Conclusions DRibbles containing specific viral antigens are an efficient ex vivo activator of human antigen-specific memory T cells specific for those antigens. This function could be enhanced by combining with Poly(I:C), CD40 ligand, and GM-CSF. This study ...
-
6تقرير
المؤلفون: Sunay, Melek, Marincola, Francesco, Khleif, Samir N, Silverstein, Samuel C, Fox, Bernard A, Galon, Jerome, Emens, Leisha A
مصطلحات موضوعية: Tumor microenvironment, Immunotherapy, Cancer, Tumor immunology, Suppressor cells, Immunoscore
الوصف: The Workshop associated with the 27th Annual Meeting of the Society for Immunotherapy of Cancer (SITC), North Bethesda, MD, October 24-25, 2012 focused on targeting the tumor microenvironment as part of an integrative approach to immune-based cancer therapy.
-
7تقرير
المؤلفون: Ascierto, Paolo A, Grimaldi, Antonio M, Acquavella, Nicolas, Borgognoni, Lorenzo, Calabrò, Luana, Cascinelli, Natale, Cesano, Alessandra, Del Vecchio, Michele, Eggermont, Alexander M, Faries, Mark, Ferrone, Soldano, Fox, Bernard A, Gajewski, Thomas F, Galon, Jérôme, Gnjatic, Sacha, Gogas, Helen, Kashani-Sabet, Mohammed, Kaufman, Howard L, Larkin, James, Lo, Roger S, Mantovani, Alberto, Margolin, Kim, Melief, Cornelis, McArthur, Grant, Palmieri, Giuseppe, Puzanov, Igor, Ribas, Antoni, Seliger, Barbara, Sosman, Jeff, Suenaert, Peter, Tarhini, Ahmad A, Trinchieri, Giorgio, Vidal-Vanaclocha, Fernando, Wang, Ena, Ciliberto, Gennaro, Mozzillo, Nicola, Marincola, Francesco M, Thurin, Magdalena
الوصف: Recent insights into the genetic and somatic aberrations have initiated a new era of rapidly evolving targeted and immune-based treatments for melanoma. After decades of unsuccessful attempts to finding a more effective cure in the treatment of melanoma now we have several drugs active in melanoma. The possibility to use these drugs in combination to improve responses to overcome the resistance, to potentiate the action of immune system with the new immunomodulating antibodies, and identification of biomarkers that can predict the response to a particular therapy represent new concepts and approaches in the clinical management of melanoma. The third “Melanoma Research: “A bridge from Naples to the World” meeting, shortened as “Bridge Melanoma Meeting” took place in Naples, December 2 to 4 th , 2012. The four topics of discussion at this meeting were: advances in molecular profiling and novel biomarkers, combination therapies, novel concepts toward integrating biomarkers and therapies into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage, and the knowledge gained from the biology of tumor microenvironment across different tumors as a bridge to impact on prognosis and response to therapy in melanoma. This international congress gathered more than 30 international faculty members who in an interactive atmosphere which stimulated discussion and exchange of their experience regarding the most recent advances in research and clinical management of melanoma patients.
-
8تقرير
المؤلفون: Ascierto, Paolo A, Grimaldi, Antonio M, Curti, Brendan, Faries, Mark B, Ferrone, Soldano, Flaherty, Keith, Fox, Bernard A, Gajewski, Thomas F, Gershenwald, Jeffrey E, Gogas, Helen, Grossmann, Kenneth, Hauschild, Axel, Hodi, F, Kefford, Richard, Kirkwood, John M, Leachmann, Sancy, Maio, Michele, Marais, Richard, Palmieri, Giuseppe, Morton, Donald L, Ribas, Antoni, Stroncek, David F, Stewart, Rodney, Wang, Ena, Mozzillo, Nicola, Marincola, Franco M
الوصف: After more than 30 years, landmark progress has been made in the treatment of cancer, and melanoma in particular, with the success of new molecules such as ipilimumab, vemurafenib and active specific immunization. After the first congress in December 2010, the second edition of “Melanoma Research: a bridge from Naples to the World” meeting, organized by Paolo A. Ascierto (INT, Naples, Italy), Francesco M. Marincola (NIH, Bethesda, USA), and Nicola Mozzillo (INT, Naples, Italy) took place in Naples, on 5–6 December 2011. We have identified four new topics of discussion: Innovative Approaches in Prevention, Diagnosis and Surgical Treatment, New Pathways and Targets in Melanoma: An Update about Immunotherapy, and Combination Strategies. This international congress gathered more than 30 international faculty members and was focused on recent advances in melanoma molecular biology, immunology and therapy, and created an interactive atmosphere which stimulated discussion of new approaches and strategies in the field of melanoma.
-
9تقرير
المؤلفون: Winter, Hauke, van den Engel, Natasja K, Rüttinger, Dominik, Schmidt, Jürgen, Schiller, Matthias, Poehlein, Christian H, Löhe, Florian, Fox, Bernard A, Jauch, Karl-Walter, Hatz, Rudolf A, Hu, Hong-Ming
الوصف: Background The mechanisms by which tumor-specific T cells induce regression of established metastases are not fully characterized. In using the poorly immunogenic B16BL6-D5 (D5) melanoma model we reported that T cell-mediated tumor regression can occur independently of perforin, IFN-γ or the combination of both. Characterization of regressing pulmonary metastases identified macrophages as a major component of the cells infiltrating the tumor after adoptive transfer of effector T cells. This led us to hypothesize that macrophages played a central role in tumor regression following T-cell transfer. Here, we sought to determine the factors responsible for the infiltration of macrophages at the tumor site. Methods These studies used the poorly immunogenic D5 melanoma model. Tumor-specific effector T cells, generated from tumor vaccine-draining lymph nodes (TVDLN), were used for adoptive immunotherapy and in vitro analysis of chemokine expression. Cellular infiltrates into pulmonary metastases were determined by immunohistochemistry. Chemokine expression by the D5 melanoma following co-culture with T cells, IFN-γ or TNF-α was determined by RT-PCR and ELISA. Functional activity of chemokines was confirmed using a macrophage migration assay. T cell activation of macrophages to release nitric oxide (NO) was determined using GRIES reagent. Results We observed that tumor-specific T cells with a type 1 cytokine profile also expressed message for and secreted RANTES, MIP-1α and MIP-1β following stimulation with specific tumor. Unexpectedly, D5 melanoma cells cultured with IFN-γ or TNF-α, two type 1 cytokines expressed by therapeutic T cells, secreted Keratinocyte Chemoattractant (KC), MCP-1, IP-10 and RANTES and expressed mRNA for MIG. The chemokines released by T cells and cytokine-stimulated tumor cells were functional and induced migration of the DJ2PM macrophage cell line. Additionally, tumor-specific stimulation of wt or perforin-deficient (PKO) effector T cells induced macrophages to secrete nitric oxide ...
-
10تقرير
المؤلفون: Winter, Hauke, van den Engel, Natasja K, Poehlein, Christian H, Hatz, Rudolf A, Fox, Bernard A, Hu, Hong-Ming
الوصف: Background Previously, we reported that adoptively transferred perforin k/o (PKO), and IFN-γ k/o (GKO), or perforin/IFN-γ double k/o (PKO/GKO) effector T cells mediated regression of B16BL6-D5 (D5) pulmonary metastases and showed that TNF receptor signaling played a critical role in mediating tumor regression. In this report we investigated the role of lymphotoxin-α (LT-α) as a potential effector molecules of tumor-specific effector T cells. Methods Effector T cells were generated from tumor vaccine-draining lymph node (TVDLN) of wt, GKO, LT-α deficient (LKO), or PKO/GKO mice and tested for their ability to mediate regression of D5 pulmonary metastases in the presence or absence of LT-βR-Fc fusion protein or anti-IFN-γ antibody. Chemokine production by D5 tumor cells was determined by ELISA, RT-PCR and Chemotaxis assays. Results Stimulated effector T cells from wt, GKO, or PKO/GKO mice expressed ligands for LT-β receptor (LT-βR). D5 tumor cells were found to constitutively express the LT-βR. Administration of LT-βR-Fc fusion protein completely abrogated the therapeutic efficacy of GKO or PKO/GKO but not wt effector T cells (p < 0.05). Consistent with this observation, therapeutic efficacy of effector T cells deficient in LT-α, was greatly reduced when IFN-γ production was neutralized. While recombinant LT-α1β2 did not induce apoptosis of D5 tumor cells in vitro, it induced secretion of chemokines by D5 that promoted migration of macrophages. Conclusion The contribution of LT-α expression by effector T cells to anti-tumor activity in vivo was not discernable when wt effector T cells were studied. However, the contribution of LT-β R signaling was identified for GKO or PKO/GKO effector T cells. Since LT-α does not directly induce killing of D5 tumor cells in vitro, but does stimulate D5 tumor cells to secrete chemokines, these data suggest a model where LT-α expression by tumor-specific effector T cells interacts via cross-linking of the LT-βR on tumor cells to induce secretion of chemokines that are ...
