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Ashwini Balakrishnan, Tracy Goodpaster, Julie Randolph-Habecker, Benjamin G Hoffstrom, Florencia G Jalikis, Lisa K Koch, Carolina Berger, Paula L Kosasih, Anusha Rajan, Daniel Sommermeyer, Peggy Porter, Stanley R Riddell
PURPOSE: This study examines cell-surface ROR1 expression in human tumors and normal tissues. ROR1 is considered a promising target for cancer therapy due to putative tumor-specific expression and multiple groups are developing antibodies and/or chimeric antigen receptor-modified T cells to target ROR1. On-target, off-tumor toxicity is a challenge for most non-mutated tumor antigens, however prior studies suggest that ROR1 is absent on most normal tissues. EXPERIMENTAL DESIGN: Our studies show that published antibodies lack sensitivity to detect endogenous levels of cell-surface ROR1 by immunohistochemistry (IHC) in FFPE tissues...
November 16, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Paulina J Paszkiewicz, Simon P Fräßle, Shivani Srivastava, Daniel Sommermeyer, Michael Hudecek, Ingo Drexler, Michel Sadelain, Lingfeng Liu, Michael C Jensen, Stanley R Riddell, Dirk H Busch
The adoptive transfer of T cells that have been genetically modified to express a CD19-specific chimeric antigen receptor (CAR) is effective for treating human B cell malignancies. However, the persistence of functional CD19 CAR T cells causes sustained depletion of endogenous CD19+ B cells and hypogammaglobulinemia. Thus, there is a need for a mechanism to ablate transferred T cells after tumor eradication is complete to allow recovery of normal B cells. Previously, we developed a truncated version of the epidermal growth factor receptor (EGFRt) that is coexpressed with the CAR on the T cell surface...
November 1, 2016: Journal of Clinical Investigation
Cameron J Turtle, Laïla-Aïcha Hanafi, Carolina Berger, Michael Hudecek, Barbara Pender, Emily Robinson, Reed Hawkins, Colette Chaney, Sindhu Cherian, Xueyan Chen, Lorinda Soma, Brent Wood, Daniel Li, Shelly Heimfeld, Stanley R Riddell, David G Maloney
CD19-specific chimeric antigen receptor (CAR)-modified T cells have antitumor activity in B cell malignancies, but factors that affect toxicity and efficacy have been difficult to define because of differences in lymphodepletion and heterogeneity of CAR-T cells administered to individual patients. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a 1:1 CD4(+)/CD8(+) ratio of CAR-T cells to 32 adults with relapsed and/or refractory B cell non-Hodgkin's lymphoma after cyclophosphamide (Cy)-based lymphodepletion chemotherapy with or without fludarabine (Flu)...
September 7, 2016: Science Translational Medicine
(no author information available yet)
The Cancer Target Discovery and Development (CTD(2)) Network was established to accelerate the transformation of "Big Data" into novel pharmacologic targets, lead compounds, and biomarkers for rapid translation into improved patient outcomes. It rapidly became clear in this collaborative network that a key central issue was to define what constitutes sufficient computational or experimental evidence to support a biologically or clinically relevant finding. This article represents a first attempt to delineate the challenges of supporting and confirming discoveries arising from the systematic analysis of large-scale data resources in a collaborative work environment and to provide a framework that would begin a community discussion to resolve these challenges...
August 2016: Molecular Cancer Research: MCR
Franziska Blaeschke, Uwe Thiel, Andreas Kirschner, Melanie Thiede, Rebeca Alba Rubio, David Schirmer, Thomas Kirchner, Günther H S Richter, Sabine Mall, Richard Klar, Stanley Riddell, Dirk H Busch, Angela Krackhardt, Thomas G P Grunewald, Stefan Burdach
The endochondral bone protein Chondromodulin-I (CHM1) provides oncogene addiction in Ewing sarcoma (ES). We pre-clinically tested the targetability of CHM1 by TCR transgenic, allo-restricted, peptide specific T cells to treat ES. We previously generated allo-restricted wildtype CD8+ T cells directed against the ES specific antigen CHM1319 causing specific responses against ES. However, utilization of these cells in current therapy protocols is hampered due to high complexity in production, relatively low cell numbers, and rapid T cell exhaustion...
July 12, 2016: Oncotarget
Gregory A Rufener, Oliver W Press, Philip Olsen, Sang Yun Lee, Michael C Jensen, Ajay K Gopal, Barbara Pender, Lihua E Budde, Jeffrey K Rossow, Damian J Green, David G Maloney, Stanley R Riddell, Brian G Till
CD20 is an attractive immunotherapy target for B-cell non-Hodgkin lymphomas, and adoptive transfer of T cells genetically modified to express a chimeric antigen receptor (CAR) targeting CD20 is a promising strategy. A theoretical limitation is that residual serum rituximab might block CAR binding to CD20 and thereby impede T cell-mediated anti-lymphoma responses. The activity of CD20 CAR-modified T cells in the presence of various concentrations of rituximab was tested in vitro and in vivo CAR-binding sites on CD20(+) tumor cells were blocked by rituximab in a dose-dependent fashion, although at 37°C blockade was incomplete at concentrations up to 200 μg/mL...
2016: Cancer Immunology Research
C J Turtle, S R Riddell, D G Maloney
Chimeric antigen receptors (CARs) comprise a tumor-targeting moiety, often in the form of a single chain variable fragment derived from a monoclonal antibody, fused to one or more intracellular T-cell signaling sequences. Lymphodepletion chemotherapy followed by infusion of T cells that are genetically modified to express a CD19-specific CAR is a promising therapy for patients with refractory CD19(+) B-cell malignancies, producing rates of complete remission that are remarkably high in acute lymphoblastic leukemia and encouraging in non-Hodgkin lymphoma and chronic lymphocytic leukemia...
September 2016: Clinical Pharmacology and Therapeutics
Xiuli Wang, Leslie L Popplewell, Jamie R Wagner, Araceli Naranjo, M Suzette Blanchard, Michelle R Mott, Adam P Norris, ChingLam W Wong, Ryan Z Urak, Wen-Chung Chang, Samer K Khaled, Tanya Siddiqi, Lihua E Budde, Jingying Xu, Brenda Chang, Nikita Gidwaney, Sandra H Thomas, Laurence J N Cooper, Stanley R Riddell, Christine E Brown, Michael C Jensen, Stephen J Forman
Myeloablative autologous hematopoietic stem cell transplantation (HSCT) is a mainstay of therapy for relapsed intermediate-grade B-cell non-Hodgkin lymphoma (NHL); however, relapse rates are high. In phase 1 studies designed to improve long-term remission rates, we administered adoptive T-cell immunotherapy after HSCT, using ex vivo-expanded autologous central memory-enriched T cells (TCM) transduced with lentivirus expressing CD19-specific chimeric antigen receptors (CARs). We present results from 2 safety/feasibility studies, NHL1 and NHL2, investigating different T-cell populations and CAR constructs...
June 16, 2016: Blood
Cameron J Turtle, Laïla-Aïcha Hanafi, Carolina Berger, Theodore A Gooley, Sindhu Cherian, Michael Hudecek, Daniel Sommermeyer, Katherine Melville, Barbara Pender, Tanya M Budiarto, Emily Robinson, Natalia N Steevens, Colette Chaney, Lorinda Soma, Xueyan Chen, Cecilia Yeung, Brent Wood, Daniel Li, Jianhong Cao, Shelly Heimfeld, Michael C Jensen, Stanley R Riddell, David G Maloney
BACKGROUND: T cells that have been modified to express a CD19-specific chimeric antigen receptor (CAR) have antitumor activity in B cell malignancies; however, identification of the factors that determine toxicity and efficacy of these T cells has been challenging in prior studies in which phenotypically heterogeneous CAR-T cell products were prepared from unselected T cells. METHODS: We conducted a clinical trial to evaluate CD19 CAR-T cells that were manufactured from defined CD4+ and CD8+ T cell subsets and administered in a defined CD4+:CD8+ composition to adults with B cell acute lymphoblastic leukemia after lymphodepletion chemotherapy...
June 1, 2016: Journal of Clinical Investigation
Dirk H Busch, Simon P Fräßle, Daniel Sommermeyer, Veit R Buchholz, Stanley R Riddell
Adoptive transfer of primary (unmodified) or genetically engineered antigen-specific T cells has demonstrated astonishing clinical results in the treatment of infections and some malignancies. Besides the definition of optimal targets and antigen receptors, the differentiation status of transferred T cells is emerging as a crucial parameter for generating cell products with optimal efficacy and safety profiles. Long-living memory T cells subdivide into phenotypically as well as functionally different subsets (e...
February 2016: Seminars in Immunology
Rebecca Gardner, David Wu, Sindhu Cherian, Min Fang, Laïla-Aïcha Hanafi, Olivia Finney, Hannah Smithers, Michael C Jensen, Stanley R Riddell, David G Maloney, Cameron J Turtle
Administration of lymphodepletion chemotherapy followed by CD19-specific chimeric antigen receptor (CAR)-modified T cells is a remarkably effective approach to treating patients with relapsed and refractory CD19(+) B-cell malignancies. We treated 7 patients with B-cell acute lymphoblastic leukemia (B-ALL) harboring rearrangement of the mixed lineage leukemia (MLL) gene with CD19 CAR-T cells. All patients achieved complete remission (CR) in the bone marrow by flow cytometry after CD19 CAR-T-cell therapy; however, within 1 month of CAR-T-cell infusion, 2 of the patients developed acute myeloid leukemia (AML) that was clonally related to their B-ALL, a novel mechanism of CD19-negative immune escape...
May 19, 2016: Blood
Lingfeng Liu, Daniel Sommermeyer, Alexandra Cabanov, Paula Kosasih, Tyler Hill, Stanley R Riddell
Adoptive immunotherapy with genetically engineered T cells has the potential to treat cancer and other diseases. The introduction of Strep-tag II sequences into specific sites in synthetic chimeric antigen receptors or natural T-cell receptors of diverse specificities provides engineered T cells with a marker for identification and rapid purification, a method for tailoring spacer length of chimeric receptors for optimal function, and a functional element for selective antibody-coated, microbead-driven, large-scale expansion...
April 2016: Nature Biotechnology
Laurie Menger, Agnes Gouble, Maria A V Marzolini, Annette Pachnio, Katharina Bergerhoff, Jake Y Henry, Julianne Smith, Martin Pule, Paul Moss, Stanley R Riddell, Sergio A Quezada, Karl S Peggs
Cytomegalovirus (CMV) infection is responsible for substantial morbidity and mortality after allogeneic hematopoietic stem cell transplant. T-cell immunity is critical for control of CMV infection, and correction of the immune deficiency induced by transplant is now clinically achievable by the adoptive transfer of donor-derived CMV-specific T cells. It is notable, however, that most clinical studies of adoptive T- cell therapy exclude patients with graft-versus-host disease (GVHD) from receiving systemic corticosteroid therapy, which impairs cellular immunity...
December 24, 2015: Blood
Alexander I Salter, Stanley R Riddell
No abstract text is available yet for this article.
October 2015: Nature Biotechnology
Shivani Srivastava, Stanley R Riddell
Despite being empirically designed based on a simple understanding of TCR signaling, T cells engineered with chimeric antigen receptors (CARs) have been remarkably successful in treating patients with advanced refractory B cell malignancies. However, many challenges remain in improving the safety and efficacy of this therapy and extending it toward the treatment of epithelial cancers. Other aspects of TCR signaling beyond those directly provided by CD3ζ and CD28 phosphorylation strongly influence a T cell's ability to differentiate and acquire full effector functions...
August 2015: Trends in Immunology
Marie Bleakley, Shelly Heimfeld, Keith R Loeb, Lori A Jones, Colette Chaney, Stuart Seropian, Ted A Gooley, Franziska Sommermeyer, Stanley R Riddell, Warren D Shlomchik
BACKGROUND: Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HCT). In mice, naive T cells (TN) cause more severe GVHD than memory T cells (TM). We hypothesized that selective depletion of TN from human allogeneic peripheral blood stem cell (PBSC) grafts would reduce GVHD and provide sufficient numbers of hematopoietic stem cells and TM to permit hematopoietic engraftment and the transfer of pathogen-specific T cells from donor to recipient, respectively...
July 1, 2015: Journal of Clinical Investigation
Carl H June, Stanley R Riddell, Ton N Schumacher
Adoptive T cell transfer for cancer, chronic infection, and autoimmunity is an emerging field that shows promise in recent trials. Using the principles of synthetic biology, advances in cell culture and genetic engineering have made it possible to generate human T cells that display desired specificities and enhanced functionalities compared with the natural immune system. The prospects for widespread availability of engineered T cells have changed dramatically, given the recent entry of the pharmaceutical industry to this arena...
March 25, 2015: Science Translational Medicine
Michael C Jensen, Stanley R Riddell
The adoptive transfer of T cells engineered to express artificial chimeric antigen receptors CARs) that target a tumor cell surface molecule has emerged as an exciting new approach for cancer immunotherapy. Clinical trials in patients with advanced B cell malignancies treated with CD19-specific CAR-modified T cells (CAR-T) have shown impressive antitumor efficacy, leading to optimism that this approach will be useful for treating common solid tumors. Because CAR-T cells recognize tumor cells independent of their expression of human leukocyte antigen (HLA) molecules, tumors that escape conventional T cells by downregulating HLA and/or mutating components of the antigen processing machinery can be eliminated...
April 2015: Current Opinion in Immunology
Stanley R Riddell
No abstract text is available yet for this article.
January 2015: Cancer Immunology Research
Carolina Berger, Daniel Sommermeyer, Michael Hudecek, Michael Berger, Ashwini Balakrishnan, Paulina J Paszkiewicz, Paula L Kosasih, Christoph Rader, Stanley R Riddell
Genetic engineering of T cells for adoptive transfer by introducing a tumor-targeting chimeric antigen receptor (CAR) is a new approach to cancer immunotherapy. A challenge for the field is to define cell surface molecules that are both preferentially expressed on tumor cells and can be safely targeted with T cells. The orphan tyrosine kinase receptor ROR1 is a candidate target for T-cell therapy with CAR-modified T cells (CAR-T cells) because it is expressed on the surface of many lymphatic and epithelial malignancies and has a putative role in tumor cell survival...
February 2015: Cancer Immunology Research
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