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https://www.readbyqxmd.com/read/28805662/clinical-and-immunological-responses-after-cd30-specific-chimeric-antigen-receptor-redirected-lymphocytes
#1
Carlos A Ramos, Brandon Ballard, Huimin Zhang, Olga Dakhova, Adrian P Gee, Zhuyong Mei, Mrinalini Bilgi, Meng-Fen Wu, Hao Liu, Bambi Grilley, Catherine M Bollard, Bill H Chang, Cliona M Rooney, Malcolm K Brenner, Helen E Heslop, Gianpietro Dotti, Barbara Savoldo
BACKGROUND: Targeting CD30 with monoclonal antibodies in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) has had profound clinical success. However, adverse events, mainly mediated by the toxin component of the conjugated antibodies, cause treatment discontinuation in many patients. Targeting CD30 with T cells expressing a CD30-specific chimeric antigen receptor (CAR) may reduce the side effects and augment antitumor activity. METHODS: We conducted a phase I dose escalation study in which 9 patients with relapsed/refractory HL or ALCL were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR (CD30...
August 14, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28783452/off-the-shelf-virus-specific-t-cells-to-treat-bk-virus-human-herpesvirus-6-cytomegalovirus-epstein-barr-virus-and-adenovirus-infections-after-allogeneic-hematopoietic-stem-cell-transplantation
#2
Ifigeneia Tzannou, Anastasia Papadopoulou, Swati Naik, Kathryn Leung, Caridad A Martinez, Carlos A Ramos, George Carrum, Ghadir Sasa, Premal Lulla, Ayumi Watanabe, Manik Kuvalekar, Adrian P Gee, Meng-Fen Wu, Hao Liu, Bambi J Grilley, Robert A Krance, Stephen Gottschalk, Malcolm K Brenner, Cliona M Rooney, Helen E Heslop, Ann M Leen, Bilal Omer
Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to recipients of HSCT as an immediately available off-the-shelf product. Patient and Methods We generated a bank of VSTs that recognized five common viral pathogens: Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6)...
August 7, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28676343/treatment-of-acute-myeloid-leukemia-with-t-cells-expressing-chimeric-antigen-receptors-directed-to-c-type-lectin-like-molecule-1
#3
Haruko Tashiro, Tim Sauer, Thomas Shum, Kathan Parikh, Maksim Mamonkin, Bilal Omer, Rayne H Rouce, Premal Lulla, Cliona M Rooney, Stephen Gottschalk, Malcolm K Brenner
The successful immunotherapy of acute myeloid leukemia (AML) has been hampered because most potential antigenic targets are shared with normal hematopoietic stem cells (HSCs), increasing the risk of sustained and severe hematopoietic toxicity following treatment. C-type lectin-like molecule 1 (CLL-1) is a membrane glycoprotein expressed by >80% of AML but is absent on normal HSCs. Here we describe the development and evaluation of CLL-1-specific chimeric antigen receptor T cells (CLL-1.CAR-Ts) and we demonstrate their specific activity against CLL-1(+) AML cell lines as well as primary AML patient samples in vitro...
July 1, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28602436/car-t-cells-administered-in-combination-with-lymphodepletion-and-pd-1-inhibition-to-patients-with-neuroblastoma
#4
Andras Heczey, Chrystal U Louis, Barbara Savoldo, Olga Dakhova, April Durett, Bambi Grilley, Hao Liu, Mengfeng F Wu, Zhuyong Mei, Adrian Gee, Birju Mehta, Huimin Zhang, Nadia Mahmood, Haruko Tashiro, Helen E Heslop, Gianpietro Dotti, Cliona M Rooney, Malcolm K Brenner
Targeting disialoganglioside (GD2) on neuroblastoma (NB) with T cells expressing a first-generation chimeric antigen receptor (CAR) was safe, but the cells had poor expansion and long-term persistence. We developed a third-generation GD2-CAR (GD2-CAR3) and hypothesized that GD2-CAR3 T cells (CARTs) would be safe and effective. This phase 1 study enrolled relapsed or refractory NB patients in three cohorts. Cohort 1 received CART alone, cohort 2 received CARTs plus cyclophosphamide and fludarabine (Cy/Flu), and cohort 3 was treated with CARTs, Cy/Flu, and a programmed death-1 (PD-1) inhibitor...
June 8, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28550199/comprehensive-approach-for-identifying-the-t-cell-subset-origin-of-cd3-and-cd28-antibody-activated-chimeric-antigen-receptor-modified-t-cells
#5
Michael Schmueck-Henneresse, Bilal Omer, Thomas Shum, Haruko Tashiro, Maksim Mamonkin, Natalia Lapteva, Sandhya Sharma, Lisa Rollins, Gianpietro Dotti, Petra Reinke, Hans-Dieter Volk, Cliona M Rooney
The outcome of therapy with chimeric Ag receptor (CAR)-modified T cells is strongly influenced by the subset origin of the infused T cells. However, because polyclonally activated T cells acquire a largely CD45RO(+)CCR7(-) effector memory phenotype after expansion, regardless of subset origin, it is impossible to know which subsets contribute to the final T cell product. To determine the contribution of naive T cell, memory stem T cell, central memory T cell, effector memory T cell, and terminally differentiated effector T cell populations to the CD3 and CD28-activated CAR-modified T cells that we use for therapy, we followed the fate and function of individually sorted CAR-modified T cell subsets after activation with CD3 and CD28 Abs (CD3/28), transduction and culture alone, or after reconstitution into the relevant subset-depleted population...
July 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28426845/her2-specific-chimeric-antigen-receptor-modified-virus-specific-t-cells-for-progressive-glioblastoma-a-phase-1-dose-escalation-trial
#6
Nabil Ahmed, Vita Brawley, Meenakshi Hegde, Kevin Bielamowicz, Mamta Kalra, Daniel Landi, Catherine Robertson, Tara L Gray, Oumar Diouf, Amanda Wakefield, Alexia Ghazi, Claudia Gerken, Zhongzhen Yi, Aidin Ashoori, Meng-Fen Wu, Hao Liu, Cliona Rooney, Gianpietro Dotti, Adrian Gee, Jack Su, Yvonne Kew, David Baskin, Yi Jonathan Zhang, Pamela New, Bambi Grilley, Milica Stojakovic, John Hicks, Suzanne Z Powell, Malcolm K Brenner, Helen E Heslop, Robert Grossman, Winfried S Wels, Stephen Gottschalk
Importance: Glioblastoma is an incurable tumor, and the therapeutic options for patients are limited. Objective: To determine whether the systemic administration of HER2-specific chimeric antigen receptor (CAR)-modified virus-specific T cells (VSTs) is safe and whether these cells have antiglioblastoma activity. Design, Setting, and Participants: In this open-label phase 1 dose-escalation study conducted at Baylor College of Medicine, Houston Methodist Hospital, and Texas Children's Hospital, patients with progressive HER2-positive glioblastoma were enrolled between July 25, 2011, and April 21, 2014...
August 1, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28183713/vaccination-targeting-native-receptors-to-enhance-the-function-and-proliferation-of-chimeric-antigen-receptor-car-modified-t-cells
#7
Miyuki Tanaka, Haruko Tashiro, Bilal Omer, Natasha Lapteva, Jun Ando, Minhtran Ngo, Birju Mehta, Gianpietro Dotti, Paul R Kinchington, Ann M Leen, Claudia Rossig, Cliona M Rooney
Purpose: The multiple mechanisms used by solid tumors to suppress tumor-specific immune responses are a major barrier to the success of adoptively transferred tumor-specific T cells. As viruses induce potent innate and adaptive immune responses, we hypothesized that the immunogenicity of viruses could be harnessed for the treatment of solid tumors if virus-specific T cells (VST) were modified with tumor-specific chimeric antigen receptors (CAR). We tested this hypothesis using VZV-specific T cells (VZVST) expressing a CAR for GD2, a disialoganglioside expressed on neuroblastoma and certain other tumors, so that the live-attenuated VZV vaccine could be used for in vivo stimulation...
July 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28129119/improving-chimeric-antigen-receptor-modified-t-cell-function-by-reversing-the-immunosuppressive-tumor-microenvironment-of-pancreatic-cancer
#8
Somala Mohammed, Sujita Sukumaran, Pradip Bajgain, Norihiro Watanabe, Helen E Heslop, Cliona M Rooney, Malcolm K Brenner, William E Fisher, Ann M Leen, Juan F Vera
The adoptive transfer of T cells redirected to tumor-associated antigens via transgenic expression of chimeric antigen receptors (CARs) has produced tumor responses, even in patients with refractory diseases. To target pancreatic cancer, we generated CAR T cells directed against prostate stem cell antigen (PSCA) and demonstrated specific tumor lysis. However, pancreatic tumors employ immune evasion strategies such as the production of inhibitory cytokines, which limit CAR T cell persistence and function...
January 4, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27873282/ebv-directed-t-cell-therapeutics-for-ebv-associated-lymphomas
#9
Lauren P McLaughlin, Stephen Gottschalk, Cliona M Rooney, Catherine M Bollard
Epstein Barr virus (EBV) is a human gamma herpes virus that establishes latency in B cells after primary infection. EBV generally only causes a mild, self-limiting viral illness but is also associated with several malignancies including posttransplantation lymphoproliferative disorder in the immunosuppressed host as well as Hodgkin and non-Hodgkin lymphoma in the immune competent host. The expression of EBV antigens by lymphoma has important applications as targets for adoptive T cell therapy. However, as many lymphomas only express subdominant EBV antigens that are less immunogenic, novel strategies are needed to manufacture EBV-specific T cell products specific for Latent Membrane Protein 1 (LMP1) and LMP2, which are expressed in lymphomas with type II and III latency...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27783956/highly-efficient-genome-editing-of-murine-and-human-hematopoietic-progenitor-cells-by-crispr-cas9
#10
Michael C Gundry, Lorenzo Brunetti, Angelique Lin, Allison E Mayle, Ayumi Kitano, Dimitrios Wagner, Joanne I Hsu, Kevin A Hoegenauer, Cliona M Rooney, Margaret A Goodell, Daisuke Nakada
Our understanding of the mechanisms that regulate hematopoietic stem/progenitor cells (HSPCs) has been advanced by the ability to genetically manipulate mice; however, germline modification is time consuming and expensive. Here, we describe fast, efficient, and cost-effective methods to directly modify the genomes of mouse and human HSPCs using the CRISPR/Cas9 system. Using plasmid and virus-free delivery of guide RNAs alone into Cas9-expressing HSPCs or Cas9-guide RNA ribonucleoprotein (RNP) complexes into wild-type cells, we have achieved extremely efficient gene disruption in primary HSPCs from mouse (>60%) and human (∼75%)...
October 25, 2016: Cell Reports
https://www.readbyqxmd.com/read/27270177/clinical-responses-with-t-lymphocytes-targeting-malignancy-associated-%C3%AE%C2%BA-light-chains
#11
Carlos A Ramos, Barbara Savoldo, Vicky Torrano, Brandon Ballard, Huimin Zhang, Olga Dakhova, Enli Liu, George Carrum, Rammurti T Kamble, Adrian P Gee, Zhuyong Mei, Meng-Fen Wu, Hao Liu, Bambi Grilley, Cliona M Rooney, Malcolm K Brenner, Helen E Heslop, Gianpietro Dotti
BACKGROUND: Treatment of B cell malignancies with adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, also depletes normal B cells and causes severe hypogammaglobulinemia. Here, we developed a strategy to target B cell malignancies more selectively by taking advantage of B cell light Ig chain restriction. We generated a CAR that is specific for the κ light chain (κ...
July 1, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27177667/large-scale-culture-and-genetic-modification-of-human-natural-killer-cells-for-cellular-therapy
#12
Natalia Lapteva, Robin Parihar, Lisa A Rollins, Adrian P Gee, Cliona M Rooney
Recent advances in methods for the ex vivo expansion of human natural killer (NK) cells have facilitated the use of these powerful immune cells in clinical protocols. Further, the ability to genetically modify primary human NK cells following rapid expansion allows targeting and enhancement of their immune function. We have successfully adapted an expansion method for primary NK cells from peripheral blood mononuclear cells or from apheresis products in gas permeable rapid expansion devices (G-Rexes). Here, we describe an optimized protocol for rapid and robust NK cell expansion as well as a method for highly efficient retroviral transduction of these ex vivo expanded cells...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/26920464/adoptive-immunotherapy-for-primary-immunodeficiency-disorders-with-virus-specific-t-lymphocytes
#13
Swati Naik, Sarah K Nicholas, Caridad A Martinez, Ann M Leen, Patrick J Hanley, Steven M Gottschalk, Cliona M Rooney, I Celine Hanson, Robert A Krance, Elizabeth J Shpall, Conrad R Cruz, Persis Amrolia, Giovanna Lucchini, Nancy Bunin, Jennifer Heimall, Orly R Klein, Andrew R Gennery, Mary A Slatter, Mark A Vickers, Jordan S Orange, Helen E Heslop, Catherine M Bollard, Michael D Keller
BACKGROUND: Viral infections are a leading fatal complication for patients with primary immunodeficiencies (PIDs) who require hematopoietic stem cell transplantation (HSCT). Use of virus-specific T lymphocytes (VSTs) has been successful for the treatment and prevention of viral infections after HSCT for malignant and nonmalignant conditions. Here we describe the clinical use of VSTs in patients with PIDs at 4 centers. OBJECTIVE: We sought to evaluate the safety and efficacy of VSTs for treatment of viral infections in patients with PIDs...
May 2016: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/26473608/anti-tumor-effects-after-adoptive-transfer-of-il-12-transposon-modified-murine-splenocytes-in-the-ot-i-melanoma-mouse-model
#14
Daniel L Galvan, Richard T O'Neil, Aaron E Foster, Leslie Huye, Adham Bear, Cliona M Rooney, Matthew H Wilson
Adoptive transfer of gene modified T cells provides possible immunotherapy for patients with cancers refractory to other treatments. We have previously used the non-viral piggyBac transposon system to gene modify human T cells for potential immunotherapy. However, these previous studies utilized adoptive transfer of modified human T cells to target cancer xenografts in highly immunodeficient (NOD-SCID) mice that do not recapitulate an intact immune system. Currently, only viral vectors have shown efficacy in permanently gene-modifying mouse T cells for immunotherapy applications...
2015: PloS One
https://www.readbyqxmd.com/read/26428384/adoptive-t-cell-immunotherapy
#15
REVIEW
Stephen Gottschalk, Cliona M Rooney
Epstein-Barr virus (EBV) is associated with a range of malignancies involving B cells, T cells, natural killer (NK) cells, epithelial cells, and smooth muscle. All of these are associated with the latent life cycles of EBV, but the pattern of latency-associated viral antigens expressed in tumor cells depends on the type of tumor. EBV-specific T cells (EBVSTs) have been explored as prophylaxis and therapy for EBV-associated malignancies for more than two decades. EBVSTs have been most successful as prophylaxis and therapy for post-transplant lymphoproliferative disease (PTLD) , which expresses the full array of latent EBV antigens (type 3 latency), in hematopoietic stem-cell transplant (HSCT) recipients...
2015: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/26160910/antigen-specific-t-cell-therapies-for-cancer
#16
REVIEW
Teresa Manzo, Helen E Heslop, Cliona M Rooney
Adoptively transferred antigen-specific T cells that recognize tumor antigens through their native receptors have many potential benefits as treatment for virus-associated diseases and malignancies, due to their ability to selectively recognize tumor antigens, expand and persist to provide long-term protection. Infusions of T cells targeting Epstein-Barr virus (EBV) antigens have shown encouraging response rates in patients with post-transplant lymphoproliferative disease as well as EBV-positive lymphomas and nasopharyngeal cancer, although a recent study also showed that human papilloma virus-reactive T cells can induce complete regression of metastatic cervical cancer...
October 15, 2015: Human Molecular Genetics
https://www.readbyqxmd.com/read/25977584/inducible-caspase-9-suicide-gene-controls-adverse-effects-from-alloreplete-t-cells-after-haploidentical-stem-cell-transplantation
#17
Xiaoou Zhou, Gianpietro Dotti, Robert A Krance, Caridad A Martinez, Swati Naik, Rammurti T Kamble, April G Durett, Olga Dakhova, Barbara Savoldo, Antonio Di Stasi, David M Spencer, Yu-Feng Lin, Hao Liu, Bambi J Grilley, Adrian P Gee, Cliona M Rooney, Helen E Heslop, Malcolm K Brenner
To test the feasibility of a single T-cell manipulation to eliminate alloreactivity while sparing antiviral and antitumor T cells, we infused 12 haploidentical hematopoietic stem cell transplant patients with increasing numbers of alloreplete haploidentical T cells expressing the inducible caspase 9 suicide gene (iC9-T cells). We determined whether the iC9-T cells produced immune reconstitution and if any resultant graft-versus-host disease (GVHD) could be controlled by administration of a chemical inducer of dimerization (CID; AP1903/Rimiducid)...
June 25, 2015: Blood
https://www.readbyqxmd.com/read/25940712/tumor-indoleamine-2-3-dioxygenase-ido-inhibits-cd19-car-t-cells-and-is-downregulated-by-lymphodepleting-drugs
#18
Soranobu Ninomiya, Neeharika Narala, Leslie Huye, Shigeki Yagyu, Barbara Savoldo, Gianpietro Dotti, Helen E Heslop, Malcolm K Brenner, Cliona M Rooney, Carlos A Ramos
Although T cells expressing CD19-specific chimeric antigen receptors (CARs) are a promising new therapy for B-cell malignancies, objective responses are observed at lower frequencies in patients with lymphoma than in those with acute B-cell leukemia. We postulated that the tumor microenvironment suppresses CAR-expressing T cells (CARTs) through the activity of indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme that converts tryptophan into metabolites that inhibit T -: cell activity. To investigate the effects of tumor IDO on CD19-CART therapy, we used a xenograft lymphoma model expressing IDO as a transgene...
June 18, 2015: Blood
https://www.readbyqxmd.com/read/25929473/housing-choices-and-care-home-design-for-people-with-dementia
#19
Karim Hadjri, Cliona Rooney, Verity Faith
This article reviews the current state of housing for people with dementia by exploring housing choices available to this group, and identifying potential issues with design of care homes. Older people who wish to age in place are faced with the challenge of adapting their domestic environment to ensure independence, accessibility, and social connectivity. This is even more challenging for people with dementia who continue to live at home, given the risks of self-harm and getting lost. More imaginative and inclusive forms of collective housing are needed...
2015: HERD
https://www.readbyqxmd.com/read/25925682/cmv-specific-t-cells-generated-from-na%C3%A3-ve-t-cells-recognize-atypical-epitopes-and-may-be-protective-in-vivo
#20
Patrick J Hanley, Jan J Melenhorst, Sarah Nikiforow, Phillip Scheinberg, James W Blaney, Gail Demmler-Harrison, C Russell Cruz, Sharon Lam, Robert A Krance, Kathryn S Leung, Caridad A Martinez, Hao Liu, Daniel C Douek, Helen E Heslop, Cliona M Rooney, Elizabeth J Shpall, A John Barrett, John R Rodgers, Catherine M Bollard
Adoptive transfer of cytomegalovirus (CMV)-specific T cells derived from adult seropositive donors can effectively restore antiviral immunity after transplantation. However, CMV-seronegative donors lack CMV-specific memory T cells, which restricts the availability of virus-specific T cells for immunoprophylaxis. We demonstrate the feasibility of deriving CMV-specific T cells from naïve cells for T cell therapy. Naïve T cells primed to recognize CMV were restricted to different, atypical epitopes than T cells derived from CMV-seropositive individuals; however, these two cell populations had similar avidities...
April 29, 2015: Science Translational Medicine
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