The Experts below are selected from a list of 324 Experts worldwide ranked by ideXlab platform
Steven A Rosenberg - One of the best experts on this subject based on the ideXlab platform.
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metastasectomy following immunotherapy with adoptive Cell Transfer for patients with advanced melanoma
Annals of Surgical Oncology, 2017Co-Authors: Nicholas D Klemen, Steven A Rosenberg, Paul L Feingold, Stephanie L Goff, Marybeth S Hughes, Udai S Kammula, James Chihhsin Yang, David S Schrump, Richard M SherryAbstract:Background Immunotherapeutic treatment strategies including adoptive Cell Transfer (ACT) for metastatic melanoma are capable of mediating complete and durable responses, as well as partial responses and prolonged disease stabilization. Unfortunately, many patients ultimately develop progressive disease. The role of salvage metastasectomy in managing these patients has not been evaluated.
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Cell Transfer immunotherapy for metastatic solid cancer—what clinicians need to know
Nature reviews. Clinical oncology, 2011Co-Authors: Steven A RosenbergAbstract:Cancer immunotherapy using the adoptive Transfer of autologous tumor-infiltrating lymphocytes results in objective cancer regression in 49-72% of patients with metastatic melanoma. In a pilot trial combining Cell Transfer with a maximum lymphodepleting regimen, complete durable responses were seen in 40% of patients, with complete responses ongoing beyond 3 to 7 years. Current approaches to Cell Transfer therapy using autologous Cells genetically engineered to express conventional or chimeric T-Cell receptors have mediated cancer regression in patients with metastatic melanoma, synovial sarcoma, neuroblastoma and refractory lymphoma. Adoptive Cell Transfer immunotherapy is a rapidly developing new approach to the therapy of metastatic cancer in humans. This Review will emphasize the current available applications of Cell Transfer immunotherapy for patients with cancer.
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Cell Transfer immunotherapy for metastatic solid cancer what clinicians need to know
Nature Reviews Clinical Oncology, 2011Co-Authors: Steven A RosenbergAbstract:Cancer immunotherapy using the adoptive Transfer of autologous tumor-infiltrating lymphocytes results in objective cancer regression in 49-72% of patients with metastatic melanoma. In a pilot trial combining Cell Transfer with a maximum lymphodepleting regimen, complete durable responses were seen in 40% of patients, with complete responses ongoing beyond 3 to 7 years. Current approaches to Cell Transfer therapy using autologous Cells genetically engineered to express conventional or chimeric T-Cell receptors have mediated cancer regression in patients with metastatic melanoma, synovial sarcoma, neuroblastoma and refractory lymphoma. Adoptive Cell Transfer immunotherapy is a rapidly developing new approach to the therapy of metastatic cancer in humans. This Review will emphasize the current available applications of Cell Transfer immunotherapy for patients with cancer.
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durable complete responses in heavily pretreated patients with metastatic melanoma using t Cell Transfer immunotherapy
Clinical Cancer Research, 2011Co-Authors: Steven A Rosenberg, Marybeth S Hughes, Udai S Kammula, James Chihhsin Yang, Richard M Sherry, Giao Q Phan, Deborah Citrin, Nicholas P Restifo, Paul F Robbins, John R WunderlichAbstract:Purpose: Most treatments for patients with metastatic melanoma have a low rate of complete regression and thus overall survival in these patients is poor. We investigated the ability of adoptive Cell Transfer utilizing autologous tumor-infiltrating lymphocytes (TIL) to mediate durable complete regressions in heavily pretreated patients with metastatic melanoma. Experimental Design: Ninety-three patients with measurable metastatic melanoma were treated with the adoptive Transfer of autologous TILs administered in conjunction with interleukin-2 following a lymphodepleting preparative regimen on three sequential clinical trials. Ninety-five percent of these patients had progressive disease following a prior systemic treatment. Median potential follow-up was 62 months. Results: Objective response rates by Response Evaluation Criteria in Solid Tumors (RECIST) in the 3 trials using lymphodepleting preparative regimens (chemotherapy alone or with 2 or 12 Gy irradiation) were 49%, 52%, and 72%, respectively. Twenty of the 93 patients (22%) achieved a complete tumor regression, and 19 have ongoing complete regressions beyond 3 years. The actuarial 3- and 5-year survival rates for the entire group were 36% and 29%, respectively, but for the 20 complete responders were 100% and 93%. The likelihood of achieving a complete response was similar regardless of prior therapy. Factors associated with objective response included longer telomeres of the infused Cells, the number of CD8 + CD27 + Cells infused, and the persistence of the infused Cells in the circulation at 1 month (all P 2 Conclusions: Cell Transfer therapy with autologous TILs can mediate durable complete responses in patients with metastatic melanoma and has similar efficacy irrespective of prior treatment. Clin Cancer Res; 17(13); 4550–7. ©2011 AACR .
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Adoptive Cell Transfer therapy.
Seminars in oncology, 2007Co-Authors: Mark E Dudley, Steven A RosenbergAbstract:Adoptive Cell Transfer therapy has developed into a potent and effective treatment for patients with metastatic melanoma. Current application of this therapy relies on the ex vivo generation of highly active, highly avid tumor-reactive lymphocyte cultures from endogenous tumor infiltrating lymphocytes or on the genetic engineering of Cells using antigen receptor genes to express de novo tumor antigen recognition. When autologous anti-tumor lymphocyte cultures are administered to patients with high-dose interleukin (IL)-2 following a lymphodepleting conditioning regimen, the Cells can expand in vivo, traffic to tumor, and mediate tumor regression and durable objective clinical responses. Current investigation seeks to improve the methods for generating and administering the lymphocyte cultures, and future clinical trials aim to improve durable response rates and extend the patient populations that are candidates for treatment.
David M Schauder - One of the best experts on this subject based on the ideXlab platform.
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Abstract A02: A pathogen boosted adoptive Cell Transfer immunotherapy to treat solid tumors
Controlling Inflammation in the Tumor Microenvironment, 2017Co-Authors: Gang Xin, David M Schauder, Aimin Jiang, Nikhil S Joshi, Weiguo CuiAbstract:Despite the remarkable success in treating hematological malignancies, adoptive Cell Transfer (ACT) still faces several challenges in treating solid tumor. The main stumbling blocks include insufficient quantity of tumor-specific T Cells for Transfer, impaired migration of Transferred T Cells into the tumor and the immunosuppressive microenvironment within the tumor. To overcome these problems, we designed an innovative approach that not only overcomes immunosuppression, but also induces robust anti-tumor T Cell responses in the tumor. We first genetically engineered dual-specific CD8 T Cells that can recognize both a tumor associated antigen and a bacterial antigen in vitro. Then, we treated tumor-bearing mice with ACT using a small number of the dual-specific CD8 T Cells. This was accompanied by intratumoral injection of a low dose of the bacteria, which was sufficient to break local immunosuppression. The dual-specific CD8 T Cells expanded robustly and migrated to the tumor bed in response to the infection. At the same time, the second TCR of these effector CD8 T Cells recognized tumor antigen and executed effector function, causing tumor regression. As a result of this enhanced anti-tumor effects, 60% of the treated mice successfully eradicated their solid tumor at the primary site. Our approach not only overcomes immunosuppression, but also recruits robust anti-tumor T Cell responses to the tumor. Overall, our study harnesses the power of multiple arms of the immune system with promising translational value, which can be used to target many types of solid tumors. Citation Format: Gang Xin, David Schauder, Aimin Jiang, Nikhil Joshi, Weiguo Cui. A pathogen boosted adoptive Cell Transfer immunotherapy to treat solid tumors. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A02.
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pathogen boosted adoptive Cell Transfer immunotherapy to treat solid tumors
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: David M Schauder, Weiqing Jing, Aimin Jiang, Nikhil S Joshi, Bryon D JohnsonAbstract:Because of insufficient migration and antitumor function of Transferred T Cells, especially inside the immunosuppressive tumor microenvironment (TME), the efficacy of adoptive Cell Transfer (ACT) is much curtailed in treating solid tumors. To overcome these challenges, we sought to reenergize ACT (ReACT) with a pathogen-based cancer vaccine. To bridge ACT with a pathogen, we genetically engineered tumor-specific CD8 T Cells in vitro with a second T-Cell receptor (TCR) that recognizes a bacterial antigen. We then Transferred these dual-specific T Cells in combination with intratumoral bacteria injection to treat solid tumors in mice. The dual-specific CD8 T Cells expanded vigorously, migrated to tumor sites, and robustly eradicated primary tumors. The mice cured from ReACT also developed immunological memory against tumor rechallenge. Mechanistically, we have found that this combined approach reverts the immunosuppressive TME and recruits CD8 T Cells with an increased number and killing ability to the tumors.
Pradeep K Dudeja - One of the best experts on this subject based on the ideXlab platform.
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Ion Transport Basis of Diarrhea in a Mouse Model of Adoptive T Cell Transfer Colitis
Digestive Diseases and Sciences, 2019Co-Authors: Dulari Jayawardena, Ali Nazmi, Danyvid Olivares-villagómez, Sangeeta Tyagi, Pradeep K DudejaAbstract:Background Diarrhea, a major pathological hallmark of inflammatory bowel disease, is characterized by a significant reduction in the expression and function of key intestinal ion transporters. The adoptive naïve CD4^+ T Cell Transfer colitis is an immune-based, chronic colitis mouse model which resembles human Crohn’s disease. Although mice with T Cell Transfer colitis demonstrate diarrhea, the ion transporter basis of this phenotype has not been explored. Aims/Methods In the current studies, we aimed to determine the mRNA and protein levels of the key NaCl transporters DRA and NHE3 along with the mRNA expression of other transporters in the inflamed intestine. Results Naïve CD4^+ T Cells, Transferred to Rag2 knockout mice, induced severe colonic inflammation characterized by histological damage and increased mRNA levels of cytokines in the colon with no effect in the ileum. Diarrheal phenotype was a key feature of the excised colons of mice where loose stools were evident. Our results demonstrated that the key chloride transporter DRA, mRNA, and protein levels were significantly reduced in the inflamed colon. However, expression of the key sodium hydrogen exchanger NHE3 was unaffected. The mRNA expression of other important transporters was also determined; in this regard, the sodium channel ENACα and the monocarboxylate transporters MCT1 and SMCT1 mRNA levels were also significantly lower compared to control mice. However, CFTR mRNA was not altered in the colon or ileum. Conclusions The studies conducted herein for the first time demonstrate the downregulation of important intestinal ion transporters in proximal and distal colon in T Cell Transfer colitis mouse model, providing valuable evidence for the ion transporter basis of diarrhea in this chronic model of inflammation.
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Ion Transport Basis of Diarrhea in a Mouse Model of Adoptive T Cell Transfer Colitis.
Digestive diseases and sciences, 2019Co-Authors: Dulari Jayawardena, Ali Nazmi, Danyvid Olivares-villagómez, Sangeeta Tyagi, Pradeep K DudejaAbstract:Diarrhea, a major pathological hallmark of inflammatory bowel disease, is characterized by a significant reduction in the expression and function of key intestinal ion transporters. The adoptive naive CD4+ T Cell Transfer colitis is an immune-based, chronic colitis mouse model which resembles human Crohn’s disease. Although mice with T Cell Transfer colitis demonstrate diarrhea, the ion transporter basis of this phenotype has not been explored. In the current studies, we aimed to determine the mRNA and protein levels of the key NaCl transporters DRA and NHE3 along with the mRNA expression of other transporters in the inflamed intestine. Naive CD4+ T Cells, Transferred to Rag2 knockout mice, induced severe colonic inflammation characterized by histological damage and increased mRNA levels of cytokines in the colon with no effect in the ileum. Diarrheal phenotype was a key feature of the excised colons of mice where loose stools were evident. Our results demonstrated that the key chloride transporter DRA, mRNA, and protein levels were significantly reduced in the inflamed colon. However, expression of the key sodium hydrogen exchanger NHE3 was unaffected. The mRNA expression of other important transporters was also determined; in this regard, the sodium channel ENACα and the monocarboxylate transporters MCT1 and SMCT1 mRNA levels were also significantly lower compared to control mice. However, CFTR mRNA was not altered in the colon or ileum. The studies conducted herein for the first time demonstrate the downregulation of important intestinal ion transporters in proximal and distal colon in T Cell Transfer colitis mouse model, providing valuable evidence for the ion transporter basis of diarrhea in this chronic model of inflammation.
Lorenzo Galluzzi - One of the best experts on this subject based on the ideXlab platform.
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Trial Watch: Adoptive Cell Transfer for anticancer immunotherapy.
Oncoimmunology, 2014Co-Authors: Erika Vacchelli, Wolf Hervé Fridman, Jérôme Galon, Eric Tartour, Laurence Zitvogel, Guido Kroemer, Alexander Eggermont, Lorenzo GalluzziAbstract:The expression "adoptive Cell Transfer" (ACT) is commonly employed to indicate an immunotherapeutic regimen involving the isolation of autologous blood-borne or tumor-infiltrating lymphocytes, their selection/expansion/activation ex vivo, and their reinfusion into the patient, most often in the context of lymphodepleting pre-conditioning and in combination with immunostimulatory treatments. Optionally, the Cellular material for ACT is genetically manipulated before expansion to (1) target specific tumor-associated antigens; (2) endogenously express immunostimulatory molecules; and/or (3) persist for long periods upon reinfusion. Consistent efforts have been dedicated at the amelioration of this immunotherapeutic regimen throughout the past decade, resulting in the establishment of ever more efficient and safer ACT protocols. Accordingly, the number of clinical trials testing ACT in oncological indications does not cease to increase. In this Trial Watch, we summarize recent developments in this exciting area of research, covering both high-impact studies that have been published during the last 12 months and clinical trials that have been launched in the same period to evaluate the safety and therapeutic potential of ACT in cancer patients.
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Trial Watch: Adoptive Cell Transfer for anticancer immunotherapy.
Oncoimmunology, 2013Co-Authors: Erika Vacchelli, Wolf Hervé Fridman, Jérôme Galon, Eric Tartour, Laurence Zitvogel, Guido Kroemer, Alexander Eggermont, Lorenzo GalluzziAbstract:Adoptive Cell Transfer (ACT) represents a prominent form of immunotherapy against malignant diseases. ACT is conceptually distinct from dendritic Cell-based approaches (which de facto constitute Cellular vaccines) and allogeneic transplantation (which can be employed for the therapy of hematopoietic tumors) as it involves the isolation of autologous lymphocytes exhibiting antitumor activity, their expansion/activation ex vivo and their reintroduction into the patient. Re-infusion is most often performed in the context of lymphodepleting regimens (to minimize immunosuppression by host Cells) and combined with immunostimulatory interventions, such as the administration of Toll-like receptor agonists. Autologous Cells that are suitable for ACT protocols can be isolated from tumor-infiltrating lymphocytes or generated by engineering their circulating counterparts for the expression of transgenic tumor-specific T-Cell receptors. Importantly, lymphocytes can be genetically modified prior to re-infusion for increasing their persistence in vivo, boosting antitumor responses and minimizing side effects. Moreover, recent data indicate that exhausted antitumor T lymphocytes may be rejuvenated in vitro by exposing them to specific cytokine cocktails, a strategy that might considerably improve the clinical success of ACT. Following up the Trial Watch that we published on this topic in the third issue of OncoImmunology (May 2012), here we summarize the latest developments in ACT-related research, covering both high-impact studies that have been published during the last 13 months and clinical trials that have been initiated in the same period to assess the antineoplastic profile of this form of Cellular immunotherapy.
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Trial Watch: Adoptive Cell Transfer immunotherapy.
Oncoimmunology, 2012Co-Authors: Lorenzo Galluzzi, Erika Vacchelli, Alexander M.m. Eggermont, Wolf Hervé Fridman, Jérôme Galon, Catherine Sautès-fridman, Eric Tartour, Laurence Zitvogel, Guido KroemerAbstract:During the last two decades, several approaches for the activation of the immune system against cancer have been developed. These include rather unselective maneuvers such as the systemic administration of immunostimulatory agents (e.g., interleukin-2) as well as targeted interventions, encompassing highly specific monoclonal antibodies, vaccines and Cell-based therapies. Among the latter, adoptive Cell Transfer (ACT) involves the selection of autologous lymphocytes with antitumor activity, their expansion/activation ex vivo, and their reinfusion into the patient, often in the context of lymphodepleting regimens (to minimize endogenous immunosuppression). Such autologous Cells can be isolated from tumor-infiltrating lymphocytes or generated by manipulating circulating lymphocytes for the expression of tumor-specific T-Cell receptors. In addition, autologous lymphocytes can be genetically engineered to prolong their in vivo persistence, to boost antitumor responses and/or to minimize side effects. ACT has recently been shown to be associated with a consistent rate of durable regressions in melanoma and renal Cell carcinoma patients and holds great promises in several other oncological settings. In this Trial Watch, we will briefly review the scientific rationale behind ACT and discuss the progress of recent clinical trials evaluating the safety and effectiveness of adoptive Cell Transfer as an anticancer therapy.
Patrik Brundin - One of the best experts on this subject based on the ideXlab platform.
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alpha synuclein Cell to Cell Transfer and seeding in grafted dopaminergic neurons in vivo
PLOS ONE, 2012Co-Authors: Elodie Angot, Jennifer A Steiner, Carla Lema M Tome, Peter Ekstrom, Bengt Mattsson, Anders Bjorklund, Patrik BrundinAbstract:Several people with Parkinson’s disease have been treated with intrastriatal grafts of fetal dopaminergic neurons. Following autopsy, 10–22 years after surgery, some of the grafted neurons contained Lewy bodies similar to those observed in the host brain. Numerous studies have attempted to explain these findings in Cell and animal models. In Cell culture, α-synuclein has been found to Transfer from one Cell to another, via mechanisms that include exosomal transport and endocytosis, and in certain cases seed aggregation in the recipient Cell. In animal models, Transfer of α-synuclein from host brain Cells to grafted neurons has been shown, but the reported frequency of the event has been relatively low and little is known about the underlying mechanisms as well as the fate of the Transferred α-synuclein. We now demonstrate frequent Transfer of α-synuclein from a rat brain engineered to overexpress human α-synuclein to grafted dopaminergic neurons. Further, we show that this model can be used to explore mechanisms underlying Cell-to-Cell Transfer of α-synuclein. Thus, we present evidence both for the involvement of endocytosis in α-synuclein uptake in vivo, and for seeding of aggregation of endogenous α-synuclein in the recipient neuron by the Transferred α-synuclein. Finally, we show that, at least in a subset of the studied Cells, the transmitted α-synuclein is sensitive to proteinase K. Our new model system could be used to test compounds that inhibit Cell-to-Cell Transfer of α-synuclein and therefore might retard progression of Parkinson neuropathology.