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Treg cyclophosphamide

Troels Holz Borch, Lotte Engell-Noerregaard, Trine Zeeberg Iversen, Eva Ellebaek, Özcan Met, Morten Hansen, Mads Hald Andersen, Per Thor Straten, Inge Marie Svane
INTRODUCTION: Vaccination with dendritic cells (DCs) has generally not fulfilled its promise in cancer immunotherapy due to ineffective translation of immune responses into clinical responses. A proposed reason for this is intrinsic immune regulatory mechanisms, such as regulatory T cells (Tregs). A metronomic regimen of cyclophosphamide (mCy) has been shown to selectively deplete Tregs. To test this in a clinical setting, we conducted a phase I trial to evaluate the feasibility and safety of vaccination with DCs transfected with mRNA in combination with mCy in patients with metastatic malignant melanoma (MM)...
2016: Oncoimmunology
Romain Daillère, Marie Vétizou, Nadine Waldschmitt, Takahiro Yamazaki, Christophe Isnard, Vichnou Poirier-Colame, Connie P M Duong, Caroline Flament, Patricia Lepage, Maria Paula Roberti, Bertrand Routy, Nicolas Jacquelot, Lionel Apetoh, Sonia Becharef, Sylvie Rusakiewicz, Philippe Langella, Harry Sokol, Guido Kroemer, David Enot, Antoine Roux, Alexander Eggermont, Eric Tartour, Ludger Johannes, Paul-Louis Woerther, Elisabeth Chachaty, Jean-Charles Soria, Encouse Golden, Silvia Formenti, Magdalena Plebanski, Mutsa Madondo, Philip Rosenstiel, Didier Raoult, Vincent Cattoir, Ivo Gomperts Boneca, Mathias Chamaillard, Laurence Zitvogel
The efficacy of the anti-cancer immunomodulatory agent cyclophosphamide (CTX) relies on intestinal bacteria. How and which relevant bacterial species are involved in tumor immunosurveillance, and their mechanism of action are unclear. Here, we identified two bacterial species, Enterococcus hirae and Barnesiella intestinihominis that are involved during CTX therapy. Whereas E. hirae translocated from the small intestine to secondary lymphoid organs and increased the intratumoral CD8/Treg ratio, B. intestinihominis accumulated in the colon and promoted the infiltration of IFN-γ-producing γδT cells in cancer lesions...
September 28, 2016: Immunity
Emma Eriksson, Jessica Wenthe, Sandra Irenaeus, Angelica Loskog, Gustav Ullenhag
BACKGROUND: Cancer immunotherapy can be potentiated by conditioning regimens such as cyclophosphamide, which reduces the level of regulatory T cells (tregs). However, myeloid suppressive cells are still remaining. Accordingly to previous reports, gemcitabine improves immune status of cancer patients. In this study, the role of gemcitabine was further explored to map its immunological target cells and molecules in patients with pancreatic cancer. METHODS: Patient blood was investigated by flow cytometry and cytokine arrays at different time points during gemcitabine treatment...
September 29, 2016: Journal of Translational Medicine
Pierre-Louis Loyher, Juliette Rochefort, Camille Baudesson de Chanville, Pauline Hamon, Géraldine Lescaille, Chloé Bertolus, Maude Guillot-Delost, Matthew Krummel, Francois M Lemoine, Christophe Combadière, Alexandre Boissonnas
The CCL2 chemokine receptor CCR2 drives cancer by mediating recruitment of monocytes and myeloid-derived suppressor cells to the tumor microenvironment. In this study, we extend the significance of CCR2 in this setting by identifying a new role for it in mediating recruitment of CD4+ T regulatory cells (Treg). Following tumor initiation, an expanded population of CCR2+ Tregs required CCR2 expression to traffic between draining lymph nodes (dLN) and the tumor. This Treg subset was enriched in the fraction of tumor antigen-specific cells in the dLN, where they displayed an activated immunosuppressive phenotype...
September 28, 2016: Cancer Research
Martina Ahlmann, Georg Hempel
Cyclophosphamide is an alkylating agent belonging to the group of oxazaphosporines. As cyclophosphamide is in clinical use for more than 40 years, there is a lot of experience using this drug for the treatment of cancer and as an immunosuppressive agent for the treatment of autoimmune and immune-mediated diseases. Besides antimitotic and antireplicative effects, cyclophosphamide has immunosuppressive as well as immunomodulatory properties. Cyclophosphamide shows selectivity for T cells and is therefore now frequently used in tumour vaccination protocols and to control post-transplant allo-reactivity in haplo-identical unmanipulated bone marrow after transplantation...
October 2016: Cancer Chemotherapy and Pharmacology
Qiu Xia, Fang-Fang Zhang, Fei Geng, Chen-Lu Liu, Yu-Qian Wang, Ping Xu, Zhen-Zhen Lu, Yu Xie, Hui Wu, Yan Chen, Yong Zhang, Wei Kong, Xiang-Hui Yu, Hai-Hong Zhang
Fibroblast activation protein α (FAPα) is expressed in cancer-associated fibroblasts (CAFs), which are the main type of cells in the tumor microenvironment. CAFs exert immunosuppressive activity, which can weaken the effects of cancer immunotherapy and mainly account for poor outcomes with therapeutic vaccines. To better target and destroy CAFs, a FAPα vaccine using a modified vaccinia ankara (MVA) vector was constructed and used with a DNA vaccine reported in our previous work for heterologous prime-boost immunizations in mice...
August 16, 2016: Cellular Immunology
Hila Confino, Michael Schmidt, Margalit Efrati, Ilan Hochman, Viktor Umansky, Itzhak Kelson, Yona Keisari
It has been demonstrated that aggressive in situ tumor destruction (ablation) could lead to the release of tumor antigens, which can stimulate anti-tumor immune responses. We developed an innovative method of tumor ablation based on intratumoral alpha-irradiation, diffusing alpha-emitters radiation therapy (DaRT), which efficiently ablates local tumors and enhances anti-tumor immunity. In this study, we investigated the anti-tumor potency of a treatment strategy, which combines DaRT tumor ablation with two approaches for the enhancement of anti-tumor reactivity: (1) neutralization of immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and (2) boost the immune response by the immunoadjuvant CpG...
October 2016: Cancer Immunology, Immunotherapy: CII
Soraya Zorro Manrique, Ana L Dominguez, Noweeda Mirza, Christopher D Spencer, Judy M Bradley, James H Finke, James J Lee, Larry R Pease, Sandra J Gendler, Peter A Cohen
Many cancers both evoke and subvert endogenous anti-tumor immunity. However, immunosuppression can be therapeutically reversed in subsets of cancer patients by treatments such as checkpoint inhibitors or Toll-like receptor agonists (TLRa). Moreover, chemotherapy can leukodeplete immunosuppressive host elements, including myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). We hypothesized that chemotherapy-induced leukodepletion could be immunopotentiated by co-administering TLRa to emulate a life-threatening infection...
June 21, 2016: Oncotarget
Juan C Gomez-Gelvez, Mohamed E Salama, Sherrie L Perkins, Matthew Leavitt, Kedar V Inamdar
OBJECTIVES: We evaluated the prognostic impact of cell-of-origin classification as well as intratumoral regulatory T cells (Tregs), macrophages, and microvessel density (MVD) on 115 patients (74 in the training set and 41 in the validation set) diagnosed with de novo diffuse large B-cell lymphoma (DLBCL) and uniformly treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. METHODS: The prognostic impact of Tregs, macrophages, and MVD was evaluated using FOXP3, CD68, and CD34 immunohistochemical stains, respectively...
April 2016: American Journal of Clinical Pathology
Jessica Stokes, Emely A Hoffman, Yi Zeng, Nicolas Larmonier, Emmanuel Katsanis
Advances in haploidentical bone marrow transplantation (h-BMT) have drastically broadened the treatment options for patients requiring BMT. The possibility of significantly reducing the complications resulting from graft-versus-host disease (GvHD) with the administration of post-transplant cyclophosphamide (PT-CY) has substantially improved the efficacy and applicability of T cell-replete h-BMT. However, higher frequency of disease recurrence remains a major challenge in h-BMT with PT-CY. There is a critical need to identify novel strategies to prevent GvHD while sparing the graft-versus-leukaemia (GvL) effect in h-BMT...
July 2016: British Journal of Haematology
S Denies, L Cicchelero, H de Rooster, S Daminet, I Polis, I Van de Maele, N N Sanders
Metronomic chemotherapy stimulates the immune response via depletion of regulatory T cells (Tregs) and suppresses angiogenesis by modulating the secretion of thrombospondin-1 (TSP-1) and vascular endothelial growth factor (VEGF). In this study, blood was collected from 10 healthy dogs and from 30 canine cancer patients before and 2 and 4 weeks after treatment with metronomic temozolomide (6.6 mg m(-2) ), cyclophosphamide (12.5 mg m(-2) ) or cyclophosphamide and temozolomide. The percentage of circulating CD25(+) Foxp3(+) CD4(+) Tregs and the plasma levels of TSP-1 and VEGF were measured...
March 9, 2016: Veterinary and Comparative Oncology
Xiao-Dan Han, Jian Zhou, Feng-Kuan Yu, Bai-Jun Fang, Yan-Li Zhang, Xu-Dong Wei, Yong-Ping Song
OBJECTIVE: To evaluate the efficiency and safety of rituximab and dexamethasone combined with cyclophosphamide for treating patients with relapsed and refractory immune thrombocytopenia (ITP). METHODS: Twelve patients with relapsed and refractory immune thrombocytopenia were prospectively enrolled in this study, and received rituximab 375 mg/m(2) once a week for 4 weeks, dexamethasone 40 mg once a day for consecutive 4 days, and cyclophosphamide 500 mg/m(2) biweekly for 2 weeks...
February 2016: Zhongguo Shi Yan Xue Ye Xue za Zhi
Junhua Xie, Shaoping Nie, Qiang Yu, Junyi Yin, Tao Xiong, Deming Gong, Mingyong Xie
The balance of T helper cells 17 (Th17)/regulatory T cells (Treg) plays a key role in maintaining a normal immune response. It is well-known that cyclophosphamide (CTX) applied at high dose often damages the immune system by inhibiting immune cell proliferation. In this study, the immunomodulating effects of Lactobacillus plantarum NCU116 in CTX-induced immunosuppression mice were investigated. Results showed that the levels of cytokines interleukin (IL)-17 and IL-21 were significantly increased after 10 days of treatment with a high dose of NCU116 (46...
February 17, 2016: Journal of Agricultural and Food Chemistry
Mladen Korbelik, Judit Banáth, Kyi Min Saw
Photodynamic therapy (PDT)-generated cancer vaccine represents an attractive potential application of PDT, therapeutic modality destroying targeted lesions by localized photooxidative stress. Since immunoregulatory cell activity has become recognized as a major obstacle to effective cancer immunotherapy, the present study examined their participation in the therapeutic effect of PDT cancer vaccine. Following protocols from previous studies, mouse with squamous cell carcinoma SCCVII tumors were vaccinated by SCCVII cells treated by PDT and response monitored by tumor size measurement...
2015: International Journal of Molecular Sciences
R M Rasmussen, I D Kurzman, B J Biller, A Guth, D M Vail
Maximally tolerated dose (MTD) and metronomic dose chemotherapeutic approaches alter the immune system and the angiogenic process in different yet potentially complementary ways. A combination of MTD doxorubicin (MTD-DOX) and metronomic cyclophosphamide (mCTX) protocol was evaluated for safety and effect on circulating regulatory T (Treg) cells. We found that mCTX can be safely administered with MTD-DOX in tumour-bearing dogs. Both combination DOX/mCTX and single-agent DOX resulted in significant depletions of circulating lymphocytes throughout the chemotherapy cycle without apparent selectivity for Tregs...
November 1, 2015: Veterinary and Comparative Oncology
Li-Yuan Chang, Yung-Chang Lin, Jy-Ming Chiang, Jayashri Mahalingam, Shih-Huan Su, Ching-Tai Huang, Wei-Ting Chen, Chien-Hao Huang, Wen-Juei Jeng, Yi-Cheng Chen, Shi-Ming Lin, I-Shyan Sheen, Chun-Yen Lin
Effector but not naive regulatory T cells (Treg cells) can accumulate in the peripheral blood as well as the tumor microenvironment, expand during tumor progression and be one of the main suppressors for antitumor immunity. However, the underlying mechanisms for effector Treg cell expansion in tumor are still unknown. We demonstrate that effector Treg cell-mediated suppression of antitumor CD8(+) T cells is tumor-nonspecific. Furthermore, TNFR2 expression is increased in these Treg cells by Affymetrix chip analysis which was confirmed by monoclonal antibody staining in both hepatocellular carcinoma (HCC) and colorectal cancer (CRC) patients and murine models...
October 2015: Oncoimmunology
Takahiro Tsuji, Taichi Hirano, Hiroshi Yamasaki, Hiroyuki Tuda
A 67-year-old woman was diagnosed with chronic lymphocytic leukemia (CLL) in October 2001. In August 2004, she received chemotherapy consisting of fludarabine and cyclophosphamide (FC therapy). After three cycles of FC therapy, the number of tumor cells was markedly decreased. However, anemia progressed. She was diagnosed with pure red cell aplasia (PRCA) by bone marrow examination and was successfully treated with cyclosporin A (CsA). In October 2008, anemia progressed with the exacerbation of CLL and she received three cycles of fludarabine therapy...
June 2015: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Nobuhiko Nakamura, Takeshi Hara, Masahito Shimizu, Ryoko Mabuchi, Junji Nagano, Tomohiko Ohno, Takahiro Kochi, Masaya Kubota, Yohei Shirakami, Naoe Goto, Hiroyasu Ito, Kuniaki Saito, Takuji Tanaka, Hisataka Moriwaki, Hisashi Tsurumi
Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step in the metabolism of tryptophan along the kynurenine pathway. In tumors, increased IDO activity inhibits proliferation and induces apoptosis of T cells and natural killer cells. We investigated the therapeutic potential of IDO inhibitor 1-methyl-D-tryptophan (D-1MT) with cyclophosphamide (CY) in a mouse model of lymphoma. To examine the effect of D-1MT, mice were killed on day 28. Serum concentrations of L-kynurenine and L-tryptophan were measured by high-performance liquid chromatography...
September 2015: International Journal of Hematology
Evan J Lipson, William H Sharfman, Shuming Chen, Tracee L McMiller, Theresa S Pritchard, January T Salas, Susan Sartorius-Mergenthaler, Irwin Freed, Sowmya Ravi, Hao Wang, Brandon Luber, Janice Davis Sproul, Janis M Taube, Drew M Pardoll, Suzanne L Topalian
BACKGROUND: Limited adjuvant treatment options exist for patients with high-risk surgically resected melanoma. This first-in-human study investigated the safety, tolerability and immunologic correlates of Melanoma GVAX, a lethally irradiated granulocyte-macrophage colony stimulating factor (GM-CSF)-secreting allogeneic whole-cell melanoma vaccine, administered in the adjuvant setting. METHODS: Patients with stage IIB-IV melanoma were enrolled following complete surgical resection...
2015: Journal of Translational Medicine
Junjie Wu, David J Waxman
Cancer chemotherapy using cytotoxic drugs can induce immunogenic tumor cell death; however, dosing regimens and schedules that enable single-agent chemotherapy to induce adaptive immune-dependent ablation of large, established tumors with activation of long-term immune memory have not been identified. Here, we investigate this issue in a syngeneic, implanted GL261 glioma model in immune-competent mice given cyclophosphamide on a 6-day repeating metronomic schedule. Two cycles of metronomic cyclophosphamide treatment induced sustained upregulation of tumor-associated CD8(+) cytotoxic T lymphocyte (CTL) cells, natural killer (NK) cells, macrophages, and other immune cells...
April 2015: Oncoimmunology
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