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https://www.readbyqxmd.com/read/29360643/tumor-infiltrating-brafv600e-specific-cd4-t-cells-correlated-with-complete-clinical-response-in-melanoma
#1
Joshua R Veatch, Sylvia M Lee, Matthew Fitzgibbon, I-Ting Chow, Brenda Jesernig, Thomas Schmitt, Ying Ying Kong, Julia Kargl, A McGarry Houghton, John A Thompson, Martin McIntosh, William W Kwok, Stanley R Riddell
T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune checkpoint inhibitor therapy or adoptive cell transfer. Unfortunately, most neoantigens result from random mutations and are patient specific, and some cancers contain few mutations to serve as potential antigens. We describe a patient with stage IV acral melanoma who obtained a complete response following adoptive transfer of tumor infiltrating lymphocytes (TIL). Tumor exome sequencing surprisingly revealed less than 30 somatic mutations, including oncogenic BRAF V600E...
January 23, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29311388/chimeric-antigen-receptor-t-cell-therapy-challenges-to-bench-to-bedside-efficacy
#2
REVIEW
Shivani Srivastava, Stanley R Riddell
Immunotherapy with T cells genetically modified to express chimeric Ag receptors (CARs) that target tumor-associated molecules have impressive efficacy in hematological malignancies. The field has now embraced the challenge of applying this approach to treat common epithelial malignancies, which make up the majority of cancer cases but evade immunologic attack by a variety of subversive mechanisms. In this study, we review the principles that have guided CAR T cell design and the extraordinary clinical results being achieved in B cell malignancies targeting CD19 with a single infusion of engineered T cells...
January 15, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29282496/management-of-complex-polyps-of-the-colon-and-rectum
#3
REVIEW
Fernando A Angarita, Adina E Feinberg, Stanley M Feinberg, Robert H Riddell, J Andrea McCart
PUPRPOSE: Benign polyps that are technically challenging and unsafe to remove via polypectomy are known as complex polyps. Concerns regarding safety and completeness of resection dictate they undergo advanced endoscopic techniques, such as endoscopic mucosal resection or surgery. We provide a comprehensive overview of complex polyps and current treatment options. METHODS: A review of the English literature was conducted to identifyarticles describing the management of complex polyps of the colon and rectum...
December 28, 2017: International Journal of Colorectal Disease
https://www.readbyqxmd.com/read/29176334/preclinical-optimization-of-a-cd20-specific-chimeric-antigen-receptor-vector-and-culture-conditions
#4
Sang Yun Lee, Philip Olsen, Dong Hoon Lee, Aimee L Kenoyer, Lihua E Budde, Shyril O'Steen, Damian J Green, Shelly Heimfeld, Michael C Jensen, Stanley R Riddell, Oliver W Press, Brian G Till
Chimeric antigen receptor (CAR)-based adoptive T-cell therapy is a highly promising treatment for lymphoid malignancies, and CD20 is an ideal target antigen. We previously developed a lentiviral construct encoding a third generation CD20-targeted CAR but identified several features that required additional optimization before clinical translation. We describe here several improvements, including replacement of the immunogenic murine antigen-binding moiety with a fully human domain, streamlining the transgene insert to enhance lentiviral titers, modifications to the extracellular IgG spacer that abrogate nonspecific activation resulting from binding to Fc receptors, and evaluation of CD28, 4-1BB, or CD28 and 4-1BB costimulatory domains...
November 23, 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/29038338/infectious-complications-of-cd19-targeted-chimeric-antigen-receptor-modified-t-cell-immunotherapy
#5
Joshua A Hill, Daniel Li, Kevin A Hay, Margaret L Green, Sindhu Cherian, Xueyan Chen, Stanley R Riddell, David G Maloney, Michael Boeckh, Cameron J Turtle
Lymphodepletion chemotherapy with CD19-targeted chimeric antigen receptor-modified T (CAR-T)-cell immunotherapy is a novel treatment for refractory or relapsed B-cell malignancies. Infectious complications of this approach have not been systematically studied. We evaluated infections occurring between days 0 to 90 in 133 patients treated with CD19 CAR-T cells in a phase 1/2 study. We used Poisson and Cox regression to evaluate pre- and posttreatment risk factors for infection, respectively. The cohort included patients with acute lymphoblastic leukemia (ALL; n = 47), chronic lymphocytic leukemia (n = 24), and non-Hodgkin lymphoma (n = 62)...
January 4, 2018: Blood
https://www.readbyqxmd.com/read/29025771/endothelial-activation-and-blood-brain-barrier-disruption-in-neurotoxicity-after-adoptive-immunotherapy-with-cd19-car-t-cells
#6
Juliane Gust, Kevin A Hay, Laïla-Aïcha Hanafi, Daniel Li, David Myerson, Luis F Gonzalez-Cuyar, Cecilia Yeung, W Conrad Liles, Mark Wurfel, Jose A Lopez, Junmei Chen, Dominic Chung, Susanna Harju-Baker, Tahsin Özpolat, Kathleen R Fink, Stanley R Riddell, David G Maloney, Cameron J Turtle
Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19(+) cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood-brain barrier (BBB) permeability...
October 12, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29024803/graft-derived-reconstitution-of-mucosal-associated-invariant-t-cells-after-allogeneic-hematopoietic-cell-transplantation
#7
Abir Bhattacharyya, Laïla-Aïcha Hanafi, Alyssa Sheih, Jonathan L Golob, Sujatha Srinivasan, Michael J Boeckh, Steven A Pergam, Sajid Mahmood, Kelsey K Baker, Ted A Gooley, Filippo Milano, David N Fredricks, Stanley R Riddell, Cameron J Turtle
Mucosal-associated invariant T (MAIT) cells express a semi-invariant Vα7.2(+) TCR that recognizes ligands from distinct bacterial and fungal species. In neonates, MAIT cells proliferate coincident with gastrointestinal (GI) bacterial colonization. In contrast, under noninflammatory conditions adult MAIT cells remain quiescent because of acquired regulation of TCR signaling. Effects of inflammation and the altered GI microbiota after allogeneic hematopoietic cell transplantation (HCT) on MAIT cell reconstitution have not been described...
October 9, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28924019/kinetics-and-biomarkers-of-severe-cytokine-release-syndrome-after-cd19-chimeric-antigen-receptor-modified-t-cell-therapy
#8
Kevin A Hay, Laïla-Aïcha Hanafi, Daniel Li, Juliane Gust, W Conrad Liles, Mark M Wurfel, José A López, Junmei Chen, Dominic Chung, Susanna Harju-Baker, Sindhu Cherian, Xueyan Chen, Stanley R Riddell, David G Maloney, Cameron J Turtle
Lymphodepletion chemotherapy followed by infusion of CD19-specific chimeric antigen receptor-modified (CAR) T cells has produced impressive antitumor responses in patients with refractory CD19+ B-cell malignancies but is often associated with cytokine release syndrome (CRS). Our understanding of CRS continues to evolve, and identification of the kinetics of CRS and predictive clinical and laboratory biomarkers of severity are needed to evaluate strategies to mitigate toxicity. We report the clinical presentation of and identify biomarkers of severe CRS in 133 adult patients who received CD19 CAR T cells...
November 23, 2017: Blood
https://www.readbyqxmd.com/read/28715249/durable-molecular-remissions-in-chronic-lymphocytic-leukemia-treated-with-cd19-specific-chimeric-antigen-receptor-modified-t-cells-after-failure-of-ibrutinib
#9
Cameron J Turtle, Kevin A Hay, Laïla-Aïcha Hanafi, Daniel Li, Sindhu Cherian, Xueyan Chen, Brent Wood, Arletta Lozanski, John C Byrd, Shelly Heimfeld, Stanley R Riddell, David G Maloney
Purpose We evaluated the safety and feasibility of anti-CD19 chimeric antigen receptor-modified T (CAR-T) cell therapy in patients with chronic lymphocytic leukemia (CLL) who had previously received ibrutinib. Methods Twenty-four patients with CLL received lymphodepleting chemotherapy and anti-CD19 CAR-T cells at one of three dose levels (2 × 105, 2 × 106, or 2 × 107 CAR-T cells/kg). Nineteen patients experienced disease progression while receiving ibrutinib, three were ibrutinib intolerant, and two did not experience progression while receiving ibrutinib...
September 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28541315/therapeutic-t-cell-engineering
#10
REVIEW
Michel Sadelain, Isabelle Rivière, Stanley Riddell
Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimaeric antigen receptors (CARs) are a class of synthetic receptors that reprogram lymphocyte specificity and function. CARs targeting CD19 have demonstrated remarkable potency in B cell malignancies. Engineered T cells are applicable in principle to many cancers, pending further progress to identify suitable target antigens, overcome immunosuppressive tumour microenvironments, reduce toxicities, and prevent antigen escape...
May 24, 2017: Nature
https://www.readbyqxmd.com/read/28463396/t-cell-infiltration-and-clonality-correlate-with-programmed-cell-death-protein-1-and-programmed-death-ligand-1-expression-in-patients-with-soft-tissue-sarcomas
#11
Seth M Pollack, Qianchuan He, Jennifer H Yearley, Ryan Emerson, Marissa Vignali, Yuzheng Zhang, Mary W Redman, Kelsey K Baker, Sara Cooper, Bailey Donahue, Elizabeth T Loggers, Lee D Cranmer, Matthew B Spraker, Y David Seo, Venu G Pillarisetty, Robert W Ricciotti, Benjamin L Hoch, Terrill K McClanahan, Erin Murphy, Wendy M Blumenschein, Steven M Townson, Sharon Benzeno, Stanley R Riddell, Robin L Jones
BACKGROUND: Patients with metastatic sarcomas have poor outcomes and although the disease may be amenable to immunotherapies, information regarding the immunologic profiles of soft tissue sarcoma (STS) subtypes is limited. METHODS: The authors identified patients with the common STS subtypes: leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), synovial sarcoma (SS), well-differentiated/dedifferentiated liposarcoma, and myxoid/round cell liposarcoma. Gene expression, immunohistochemistry for programmed cell death protein (PD-1) and programmed death-ligand 1 (PD-L1), and T-cell receptor Vβ gene sequencing were performed on formalin-fixed, paraffin-embedded tumors from 81 patients...
September 1, 2017: Cancer
https://www.readbyqxmd.com/read/28408462/intent-to-treat-leukemia-remission-by-cd19-car-t-cells-of-defined-formulation-and-dose-in-children-and-young-adults
#12
Rebecca A Gardner, Olivia Finney, Colleen Annesley, Hannah Brakke, Corinne Summers, Kasey Leger, Marie Bleakley, Christopher Brown, Stephanie Mgebroff, Karen S Kelly-Spratt, Virginia Hoglund, Catherine Lindgren, Assaf P Oron, Daniel Li, Stanley R Riddell, Julie R Park, Michael C Jensen
Transitioning CD19-directed chimeric antigen receptor (CAR) T cells from early-phase trials in relapsed patients to a viable therapeutic approach with predictable efficacy and low toxicity for broad application among patients with high unmet need is currently complicated by product heterogeneity resulting from transduction of undefined T-cell mixtures, variability of transgene expression, and terminal differentiation of cells at the end of culture. A phase 1 trial of 45 children and young adults with relapsed or refractory B-lineage acute lymphoblastic leukemia was conducted using a CD19 CAR product of defined CD4/CD8 composition, uniform CAR expression, and limited effector differentiation...
June 22, 2017: Blood
https://www.readbyqxmd.com/read/27852699/analysis-of-ror1-protein-expression-in-human-cancer-and-normal-tissues
#13
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 L 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 nonmutated 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 formalin-fixed, paraffin-embedded tissues...
June 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27760047/targeted-antibody-mediated-depletion-of-murine-cd19-car-t-cells-permanently-reverses-b-cell-aplasia
#14
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
https://www.readbyqxmd.com/read/27605551/immunotherapy-of-non-hodgkin-s-lymphoma-with-a-defined-ratio-of-cd8-and-cd4-cd19-specific-chimeric-antigen-receptor-modified-t-cells
#15
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
https://www.readbyqxmd.com/read/27401613/transforming-big-data-into-cancer-relevant-insight-an-initial-multi-tier-approach-to-assess-reproducibility-and-relevance
#16
(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
https://www.readbyqxmd.com/read/27281613/human-hla-a-02-01-chm1-allo-restricted-t-cell-receptor-transgenic-cd8-t-cells-specifically-inhibit-ewing-sarcoma-growth-in-vitro-and-in-vivo
#17
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
https://www.readbyqxmd.com/read/27197068/preserved-activity-of-cd20-specific-chimeric-antigen-receptor-expressing-t-cells-in-the-presence-of-rituximab
#18
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...
June 2016: Cancer Immunology Research
https://www.readbyqxmd.com/read/27170467/cd19-targeted-chimeric-antigen-receptor-modified-t-cell-immunotherapy-for-b-cell-malignancies
#19
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
https://www.readbyqxmd.com/read/27118452/phase-1-studies-of-central-memory-derived-cd19-car-t-cell-therapy-following-autologous-hsct-in-patients-with-b-cell-nhl
#20
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
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