المؤلفون: Michael C. Jensen, Leslie S. Kean, Rebecca Gardner, Stanley R. Riddell, Carolina Berger, Bruce R. Blazar, Hannah Brakke, Olivia Finney, Virginia Hoglund, Daniel J. Hunt, Scott N. Furlan, Hengqi Zheng, Alison Yu, Chris English, Audrey Baldessari, Luis Gonzalez-Cuyar, David Myerson, H. Denny Liggitt, Jessica M. Snyder, Cameron J. Turtle, Rafael Ponce, Victor Tkachev, Agne Taraseviciute

الوصف: CSF and serum levels of 21 cytokines and chemokines measured before and at indicated days after adoptive CD20 CAR T cell transfer.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::441d7e1e252feadc79d5376efb380649Test
https://doi.org/10.1158/2159-8290.22532947.v1Test

المؤلفون: Michael C. Jensen, Leslie S. Kean, Rebecca Gardner, Stanley R. Riddell, Carolina Berger, Bruce R. Blazar, Hannah Brakke, Olivia Finney, Virginia Hoglund, Daniel J. Hunt, Scott N. Furlan, Hengqi Zheng, Alison Yu, Chris English, Audrey Baldessari, Luis Gonzalez-Cuyar, David Myerson, H. Denny Liggitt, Jessica M. Snyder, Cameron J. Turtle, Rafael Ponce, Victor Tkachev, Agne Taraseviciute

الوصف: A, Schema of the CD20 CAR construct. B, Cytolytic activity of human CD19 CAR T cells (solid lines) and mock (dashed lines) T cells against 51Cr-labeled human K562 and CD19-K562 and RM B-LCL1 and B-LCL2.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::59116bbcf89a1f8e46cc7046bf48f1c5Test
https://doi.org/10.1158/2159-8290.22532959Test

المؤلفون: Michael C. Jensen, Leslie S. Kean, Rebecca Gardner, Stanley R. Riddell, Carolina Berger, Bruce R. Blazar, Hannah Brakke, Olivia Finney, Virginia Hoglund, Daniel J. Hunt, Scott N. Furlan, Hengqi Zheng, Alison Yu, Chris English, Audrey Baldessari, Luis Gonzalez-Cuyar, David Myerson, H. Denny Liggitt, Jessica M. Snyder, Cameron J. Turtle, Rafael Ponce, Victor Tkachev, Agne Taraseviciute

الوصف: Absolute numbers of RM EGFRt- (non-CAR) T cells before and at indicated days after adoptive CD20 CAR T cell transfer in the blood.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::16b5080f6679f26b862c4603e38ee382Test
https://doi.org/10.1158/2159-8290.22532956.v1Test

المؤلفون: Michael C. Jensen, Leslie S. Kean, Rebecca Gardner, Stanley R. Riddell, Carolina Berger, Bruce R. Blazar, Hannah Brakke, Olivia Finney, Virginia Hoglund, Daniel J. Hunt, Scott N. Furlan, Hengqi Zheng, Alison Yu, Chris English, Audrey Baldessari, Luis Gonzalez-Cuyar, David Myerson, H. Denny Liggitt, Jessica M. Snyder, Cameron J. Turtle, Rafael Ponce, Victor Tkachev, Agne Taraseviciute

الوصف: Serum levels of 24 cytokines and chemokines measured before and at indicated days after adoptive GFP or CD20 CAR T cell transfer in the blood.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::798940ae0e733899330fcc1436bfdeabTest
https://doi.org/10.1158/2159-8290.22532953.v1Test

المؤلفون: Michael C. Jensen, Leslie S. Kean, Rebecca Gardner, Stanley R. Riddell, Carolina Berger, Bruce R. Blazar, Hannah Brakke, Olivia Finney, Virginia Hoglund, Daniel J. Hunt, Scott N. Furlan, Hengqi Zheng, Alison Yu, Chris English, Audrey Baldessari, Luis Gonzalez-Cuyar, David Myerson, H. Denny Liggitt, Jessica M. Snyder, Cameron J. Turtle, Rafael Ponce, Victor Tkachev, Agne Taraseviciute

الوصف: A, Immunofluorescence images for CD20 (green), CD3 (red) and DAPI (blue) in R.304 before (pre, day -7) and following CD20 CAR T cell transfer (day 7 (d7)), in lymph node (LN) and brain (day 8 (d8)) and in normal RM brain. B, H&E CSF cytospin (day 8, R.304) shows marked lymphocytosis following CD20 CAR T cell transfer. C, Fraction (%) of EGFRt+ or EGFRt- CD4 an CD8 T cells expressing ï�¡4 and ï�¢1 integrins, in the blood of normal RM controls (n = 5), on day 0, pre-CD20 CAR infusion (d0, n = 4) and on day 7 or 8 (peak CD20 CAR expansion, (d7/8, n = 4)), in the CSF (on day 8 (R.304); d8, n = 1) and in the brain (on day 8 (R.304); d8, n = 1 ). * P < 0.05.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::23022081fc6cd05edc106d3439eadb30Test
https://doi.org/10.1158/2159-8290.22532950.v1Test

المؤلفون: Michael C. Jensen, Leslie S. Kean, Rebecca Gardner, Stanley R. Riddell, Carolina Berger, Bruce R. Blazar, Hannah Brakke, Olivia Finney, Virginia Hoglund, Daniel J. Hunt, Scott N. Furlan, Hengqi Zheng, Alison Yu, Chris English, Audrey Baldessari, Luis Gonzalez-Cuyar, David Myerson, H. Denny Liggitt, Jessica M. Snyder, Cameron J. Turtle, Rafael Ponce, Victor Tkachev, Agne Taraseviciute

الوصف: Antibodies and reagents used in Materials and Methods.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::53f54d8fe30f341fe49df2188b01a069Test
https://doi.org/10.1158/2159-8290.22532938.v1Test

المؤلفون: Michael C. Jensen, Leslie S. Kean, Rebecca Gardner, Stanley R. Riddell, Carolina Berger, Bruce R. Blazar, Hannah Brakke, Olivia Finney, Virginia Hoglund, Daniel J. Hunt, Scott N. Furlan, Hengqi Zheng, Alison Yu, Chris English, Audrey Baldessari, Luis Gonzalez-Cuyar, David Myerson, H. Denny Liggitt, Jessica M. Snyder, Cameron J. Turtle, Rafael Ponce, Victor Tkachev, Agne Taraseviciute

الوصف: Grading system for neurotoxicity.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3fcc0ec773dcbe8fa5fc1825120f693bTest
https://doi.org/10.1158/2159-8290.22532941Test

المؤلفون: Michael C. Jensen, Leslie S. Kean, Rebecca Gardner, Stanley R. Riddell, Carolina Berger, Bruce R. Blazar, Hannah Brakke, Olivia Finney, Virginia Hoglund, Daniel J. Hunt, Scott N. Furlan, Hengqi Zheng, Alison Yu, Chris English, Audrey Baldessari, Luis Gonzalez-Cuyar, David Myerson, H. Denny Liggitt, Jessica M. Snyder, Cameron J. Turtle, Rafael Ponce, Victor Tkachev, Agne Taraseviciute

الوصف: CD20 CAR T cell ex vivo expansion characteristics.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5fd96262e0200e8f93f7aab574d28aeeTest
https://doi.org/10.1158/2159-8290.22532944Test

المؤلفون: Hannah Brakke, Olivia Finney, Roxana Hicks, Daniel Li, Stephanie Rawlings-Rhea, Rebecca Gardner, Ben Futrell, Marisa Lopez, Michael C. Jensen, Rimas J. Orentas, Danielle Doolittle

المصدر: J Clin Invest

مصطلحات موضوعية: Male, 0301 basic medicine, Oncology, Adoptive cell transfer, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Kaplan-Meier Estimate, Hematopoietic stem cell transplantation, CD8-Positive T-Lymphocytes, Lymphocyte Activation, Immunotherapy, Adoptive, 0302 clinical medicine, Recurrence, Cytotoxic T cell, Child, Hepatitis A Virus Cellular Receptor 2, Leukemia, Receptors, Chimeric Antigen, Gene Expression Regulation, Leukemic, Remission Induction, Hematopoietic Stem Cell Transplantation, General Medicine, Aplasia, Lymphocyte Activation Gene 3 Protein, Phenotype, medicine.anatomical_structure, Child, Preschool, 030220 oncology & carcinogenesis, Female, Adult, medicine.medical_specialty, Adolescent, Antigens, CD19, Disease-Free Survival, Immunophenotyping, Young Adult, 03 medical and health sciences, Antigen, Antigens, CD, Internal medicine, medicine, Humans, B cell, Cell Proliferation, Tumor Necrosis Factor-alpha, business.industry, Infant, medicine.disease, Chimeric antigen receptor, 030104 developmental biology, Commentary, K562 Cells, business, CD8

الوصف: BACKGROUND. Chimeric antigen receptor (CAR) T cells can induce remission in highly refractory leukemia and lymphoma subjects, yet the parameters for achieving sustained relapse-free survival are not fully delineated. METHODS. We analyzed 43 pediatric and young adult subjects participating in a phase I trial of defined composition CD19 CAR T cells (ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT02028455","term_id":"NCT02028455"}}NCT02028455). CAR T cell phenotype, function, and expansion, as well as starting material T cell repertoire, were analyzed in relationship to therapeutic outcome (defined as achieving complete remission within 63 days) and duration of leukemia-free survival and B cell aplasia. RESULTS. These analyses reveal that initial therapeutic failures (n = 5) were associated with attenuated CAR T cell expansion and/or rapid attrition of functional CAR effector cells following adoptive transfer. The CAR T products were similar in phenotype and function when compared with products resulting in sustained remissions. However, the initial apheresed peripheral blood T cells could be distinguished by an increased frequency of LAG-3+/TNF-αlo CD8 T cells and, following adoptive transfer, the rapid expression of exhaustion markers. For the 38 subjects who achieved an initial sustained minimal residual disease–negative remission, 15 are still in remission, 10 of whom underwent allogenic hematopoietic stem cell transplantation (alloHSCT) following CAR T treatment. Subsequent remission durability correlated with therapeutic products having increased frequencies of TNF-α–secreting CAR CD8+ T cells, but was dependent on a sufficiently high CD19+ antigen load at time of infusion to trigger CAR T cell proliferation. CONCLUSION. These parameters have the potential to prospectively identify patients at risk for therapeutic failure and support the development of approaches to boost CAR T cell activation and proliferation in patients with low levels of CD19 antigen. TRIAL REGISTRATION. ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT02028455","term_id":"NCT02028455"}}NCT02028455. FUNDING. Partial funding for this study was provided by a Stand Up to Cancer and St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113), R01 CA136551-05, an Alex Lemonade Stand Phase I/II Infrastructure Grant, a Conquer Cancer Foundation Career Development Award, the Washington State Life Sciences Discovery Fund, the Ben Towne Foundation, the William Lawrence & Blanche Hughes Foundation, and Juno Therapeutics Inc., a Celgene Company.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a113c5e07f7fbde58d76de414a97babfTest
https://doi.org/10.1172/jci125423Test

المؤلفون: Olivia Finney, Christopher Brown, Daniel Li, Catherine Lindgren, Rebecca Gardner, Julie R. Park, Hannah Brakke, Marie Bleakley, Virginia Hoglund, Stanley R. Riddell, Corinne Summers, Michael C. Jensen, Karen S. Kelly-Spratt, Assaf P. Oron, Colleen Annesley, Stephanie Mgebroff, Kasey J. Leger

المصدر: Blood. 129:3322-3331

مصطلحات موضوعية: 0301 basic medicine, Oncology, medicine.medical_specialty, Cyclophosphamide, Clinical Trials and Observations, T-Lymphocytes, Immunology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Adverse effect, business.industry, Cell Biology, Hematology, medicine.disease, Chimeric antigen receptor, Fludarabine, Leukemia, Cytokine release syndrome, 030104 developmental biology, 030220 oncology & carcinogenesis, Chimeric Antigen Receptor T-Cell Therapy, business, CD8, medicine.drug

الوصف: 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. Products meeting all defined specifications occurred in 93% of enrolled patients. The maximum tolerated dose was 106 CAR T cells per kg, and there were no deaths or instances of cerebral edema attributable to product toxicity. The overall intent-to-treat minimal residual disease–negative (MRD−) remission rate for this phase 1 study was 89%. The MRD− remission rate was 93% in patients who received a CAR T-cell product and 100% in the subset of patients who received fludarabine and cyclophosphamide lymphodepletion. Twenty-three percent of patients developed reversible severe cytokine release syndrome and/or reversible severe neurotoxicity. These data demonstrate that manufacturing a defined-composition CD19 CAR T cell identifies an optimal cell dose with highly potent antitumor activity and a tolerable adverse effect profile in a cohort of patients with an otherwise poor prognosis. This trial was registered at www.clinicaltrials.gov as #NCT02028455.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7d7d85b58e894614d51af761bf042fdbTest
https://doi.org/10.1182/blood-2017-02-769208Test