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Consider Changing the Horse for Your CAR-T?
Wilson MH
(2018) Mol Ther 26: 1873-1874
MeSH Terms: Animals, Antigens, CD19, Heterografts, Horses, Immunoglobulin G, Immunotherapy, Adoptive, T-Lymphocytes
Added December 13, 2018
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1 Members
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7 MeSH Terms
Anti-leukemic potency of piggyBac-mediated CD19-specific T cells against refractory Philadelphia chromosome-positive acute lymphoblastic leukemia.
Saito S, Nakazawa Y, Sueki A, Matsuda K, Tanaka M, Yanagisawa R, Maeda Y, Sato Y, Okabe S, Inukai T, Sugita K, Wilson MH, Rooney CM, Koike K
(2014) Cytotherapy 16: 1257-69
MeSH Terms: Antigens, CD19, Cancer Vaccines, Cell Line, Tumor, Cell Proliferation, Culture Media, Serum-Free, Cytotoxicity, Immunologic, DNA Transposable Elements, Drug Resistance, Neoplasm, Genetic Engineering, Genetic Vectors, Humans, Immunotherapy, Adoptive, Interleukin-15, Interleukin-2, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mutation, Protein Kinase Inhibitors, Receptors, Antigen, T-Cell, Recombinant Fusion Proteins, T-Lymphocytes, TNF-Related Apoptosis-Inducing Ligand, Up-Regulation
Show Abstract · Added October 28, 2014
BACKGROUND AIMS - To develop a treatment option for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) resistant to tyrosine kinase inhibitors (TKIs), we evaluated the anti-leukemic activity of T cells non-virally engineered to express a CD19-specific chimeric antigen receptor (CAR).
METHODS - A CD19.CAR gene was delivered into mononuclear cells from 10 mL of blood of healthy donors through the use of piggyBac-transposons and the 4-D Nucleofector System. Nucleofected cells were stimulated with CD3/CD28 antibodies, magnetically selected for the CD19.CAR, and cultured in interleukin-15-containing serum-free medium with autologous feeder cells for 21 days. To evaluate their cytotoxic potency, we co-cultured CAR T cells with seven Ph(+)ALL cell lines including three TKI-resistant (T315I-mutated) lines at an effector-to-target ratio of 1:5 or lower without cytokines.
RESULTS - We obtained ∼1.3 × 10(8) CAR T cells (CD4(+), 25.4%; CD8(+), 71.3%), co-expressing CD45RA and CCR7 up to ∼80%. After 7-day co-culture, CAR T cells eradicated all tumor cells at the 1:5 and 1:10 ratios and substantially reduced tumor cell numbers at the 1:50 ratio. Kinetic analysis revealed up to 37-fold proliferation of CAR T cells during a 20-day culture period in the presence of tumor cells. On exposure to tumor cells, CAR T cells transiently and reproducibly upregulated the expression of transgene as well as tumor necrosis factor-related apoptosis-inducing ligand and interleukin-2.
CONCLUSIONS - We generated a clinically relevant number of CAR T cells from 10 mL of blood through the use of piggyBac-transposons, a 4D-Nulcleofector, and serum/xeno/tumor cell/virus-free culture system. CAR T cells exhibited marked cytotoxicity against Ph(+)ALL regardless of T315I mutation. PiggyBac-mediated CD19-specific T-cell therapy may provide an effective, inexpensive and safe option for drug-resistant Ph(+)ALL.
Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
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22 MeSH Terms
Inactivation of p53 is insufficient to allow B cells and B-cell lymphomas to survive without Dicer.
Adams CM, Eischen CM
(2014) Cancer Res 74: 3923-34
MeSH Terms: Animals, Antigens, CD19, B-Lymphocytes, Cell Survival, Cell Transformation, Neoplastic, Female, Gene Deletion, Gene Expression, Gene Silencing, Genes, myc, Lymphoma, B-Cell, Mice, Mice, Knockout, Phenotype, Ribonuclease III, Tumor Suppressor Protein p53
Show Abstract · Added May 27, 2014
Inactivation of p53, the master regulator of cellular stress and damage signals, often allows cells that should die or senesce to live. Loss of Dicer, an RNase III-like enzyme critical in microRNA biogenesis, causes embryonic lethality and activation of the p53 pathway. Several nonhematopoietic cell types that contain inactivated p53 have been shown to survive Dicer deletion, suggesting that p53 loss may protect cells from the negative consequences of Dicer deletion. However, here, we report that loss of p53 did not provide a survival advantage to B cells, as they underwent rapid apoptosis upon Dicer deletion. Moreover, a deficiency in p53 neither rescued the Dicer deletion-induced delay in Myc-driven B-cell lymphomagenesis, nor allowed a single B-cell lymphoma to develop with biallelic deletion of Dicer. A p53 deficiency did, however, restore the pre-B/B-cell phenotype and CD19 surface expression of the lymphomas that emerged in conditional Dicer knockout Eμ-myc transgenic mice. Moreover, p53 loss in transformed B cells did not confer protection from apoptosis, as Dicer deletion in established p53-null B-cell lymphomas induced apoptosis, and all of the 1,260 B-cell lymphoma clones analyzed that survived Cre-mediated Dicer deletion retained at least one allele of Dicer. Moreover, Dicer deletion in lymphomas in vivo reduced tumor burden and prolonged survival. Therefore, inactivation of p53 is insufficient to allow untransformed B cells and B-cell lymphomas to survive without Dicer, presenting a potential therapeutic opportunity for the treatment of B-cell lymphomas.
©2014 American Association for Cancer Research.
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16 MeSH Terms
Combining mTor inhibitors with rapamycin-resistant T cells: a two-pronged approach to tumor elimination.
Huye LE, Nakazawa Y, Patel MP, Yvon E, Sun J, Savoldo B, Wilson MH, Dotti G, Rooney CM
(2011) Mol Ther 19: 2239-48
MeSH Terms: Animals, Antigens, CD19, Apoptosis, B-Lymphocytes, Blotting, Western, Burkitt Lymphoma, Cell Proliferation, Cells, Cultured, Combined Modality Therapy, Drug Resistance, Neoplasm, Female, Flow Cytometry, Humans, Immunosuppressive Agents, Interferon-gamma, Lymphocyte Activation, Mice, Mice, Inbred NOD, Mice, SCID, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Receptors, Antigen, Sirolimus, T-Lymphocytes, TOR Serine-Threonine Kinases
Show Abstract · Added August 22, 2013
Despite activity as single agent cancer therapies, Rapamycin (rapa) and its rapalogs may have their greatest effects when combined with other therapeutic modalities. In addition to direct antitumor activity, rapalogs reverse multiple tumor-intrinsic immune evasion mechanisms. These should facilitate tumor-specific T cell activity, but since rapa directly inhibits effector T cells, this potential immune enhancement is lost. We hypothesized that if T cells were rendered resistant to rapa they could capitalize on its downregulation of tumor immune evasion. We therefore modified T cells with a rapa-resistant mutant of mTor, mTorRR, and directed them to B lymphomas by coexpressing a chimeric antigen receptor (CAR) for CD19 (CAR.CD19-28ζ). T cells expressing transgenic mTorRR from a piggyBac transposon maintain mTor signaling, proliferate in the presence of rapa and retain their cytotoxic function and ability to secrete interferon-γ (IFNγ) after stimulation, effector functions that were inhibited by rapa in control T cells. In combination, rapa and rapa-resistant-CAR.CD19-28ζ-expressing T cells produced greater antitumor activity against Burkitt's lymphoma and pre-B ALL cell lines in vitro than CAR.CD19-28ζ T cells or rapa alone. In conclusion, the combination of rapa and rapa-resistant, CAR.CD19-28ζ-expressing T cells may provide a novel therapy for the treatment of B cell malignancies and other cancers.
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24 MeSH Terms
PiggyBac-mediated cancer immunotherapy using EBV-specific cytotoxic T-cells expressing HER2-specific chimeric antigen receptor.
Nakazawa Y, Huye LE, Salsman VS, Leen AM, Ahmed N, Rollins L, Dotti G, Gottschalk SM, Wilson MH, Rooney CM
(2011) Mol Ther 19: 2133-43
MeSH Terms: Animals, Antigen Presentation, Antigens, CD19, Brain Neoplasms, Cell Line, Tumor, Coculture Techniques, Enzyme-Linked Immunosorbent Assay, Epstein-Barr Virus Infections, Flow Cytometry, Herpesvirus 4, Human, Humans, Immunotherapy, Male, Mice, Mice, Inbred NOD, Mice, SCID, Receptor, ErbB-2, Receptors, Antigen, Recombinant Fusion Proteins, T-Lymphocytes, Cytotoxic, Transduction, Genetic, Tumor Cells, Cultured
Show Abstract · Added August 22, 2013
Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) can be modified to function as heterologous tumor directed effector cells that survive longer in vivo than tumor directed T cells without virus specificity, due to chronic stimulation by viral antigens expressed during persistent infection in seropositive individuals. We evaluated the nonviral piggyBac (PB) transposon system as a platform for modifying EBV-CTLs to express a functional human epidermal growth factor receptor 2-specific chimeric antigen receptor (HER2-CAR) thereby directing virus-specific, gene modified CTLs towards HER2-positive cancer cells. Peripheral blood mononuclear cells (PBMCs) were nucleofected with transposons encoding a HER2-CAR and a truncated CD19 molecule for selection followed by specific activation and expansion of EBV-CTLs. HER2-CAR was expressed in ~40% of T cells after CD19 selection with retention of immunophenotype, polyclonality, and function. HER2-CAR-modified EBV-CTLs (HER2-CTLs) killed HER2-positive brain tumor cell lines in vitro, exhibited transient and reversible increases in HER2-CAR expression following antigen-specific stimulation, and stably expressed HER2-CAR beyond 120 days. Adoptive transfer of PB-modified HER2-CTLs resulted in tumor regression in a murine xenograft model. Our results demonstrate that PB can be used to redirect virus-specific CTLs to tumor targets, which should prolong tumor-specific T cell survival in vivo producing more efficacious immunotherapy.
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22 MeSH Terms
Follicular B cell trafficking within the spleen actively restricts humoral immune responses.
Hoek KL, Gordy LE, Collins PL, Parekh VV, Aune TM, Joyce S, Thomas JW, Van Kaer L, Sebzda E
(2010) Immunity 33: 254-65
MeSH Terms: Animals, Antigens, CD19, Antigens, T-Independent, B-Lymphocytes, Bone Marrow, Cell Differentiation, Cell Movement, Cells, Cultured, Immunity, Humoral, Kruppel-Like Transcription Factors, Mice, Mice, Knockout, Receptors, CCR, Spleen
Show Abstract · Added December 10, 2013
Follicular (FO) and marginal zone (MZ) B cells are maintained in distinct locations within the spleen, but the genetic basis for this separation is still enigmatic. We now report that B cell sequestration requires lineage-specific regulation of migratory receptors by the transcription factor Klf2. Moreover, using gene-targeted mice we show that altered splenic B cell migration confers a significant in vivo gain-of-function phenotype to FO B cells, including the ability to quickly respond to MZ-associated antigens and pathogens in a T cell-dependent manner. This work demonstrates that in wild-type animals, naive FO B cells are actively removed from the MZ, thus restricting their capacity to respond to blood-borne pathogens.
Copyright 2010 Elsevier Inc. All rights reserved.
1 Communities
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14 MeSH Terms
Pseudovirion particles bearing native HIV envelope trimers facilitate a novel method for generating human neutralizing monoclonal antibodies against HIV.
Hicar MD, Chen X, Briney B, Hammonds J, Wang JJ, Kalams S, Spearman PW, Crowe JE
(2010) J Acquir Immune Defic Syndr 54: 223-35
MeSH Terms: AIDS Vaccines, Amino Acid Sequence, Antibodies, Monoclonal, Antibody Specificity, Antigens, CD19, B-Lymphocytes, Cells, Cultured, Gene Expression Regulation, Green Fluorescent Proteins, HIV, Humans, Hybridomas, Immunoglobulins, Molecular Sequence Data, Protein Multimerization, Virion, env Gene Products, Human Immunodeficiency Virus, gag Gene Products, Human Immunodeficiency Virus
Show Abstract · Added August 6, 2012
Monomeric HIV envelope vaccines fail to elicit broadly neutralizing antibodies or to protect against infection. Neutralizing antibodies against HIV bind to native functionally active Env trimers on the virion surface. Gag-Env pseudovirions recapitulate the native trimer and could serve as an effective epitope presentation platform for study of the neutralizing antibody response in HIV-infected individuals. To address if pseudovirions can recapitulate native HIV virion epitope structures, we carefully characterized these particles, concentrating on the antigenic structure of the coreceptor binding site. By blue native gel shift assays, Gag-Env pseudovirions were shown to contain native trimers that were competent for binding to neutralizing monoclonal antibodies. In enzyme-linked immunosorbent assay, pseudovirions exhibited increased binding of known CD4-induced antibodies after addition of CD4. Using flow cytometric analysis, fluorescently labeled pseudovirions specifically identified a subset of antigen-specific B cells in HIV-infected subjects. Interestingly, the sequence of one of these novel human antibodies, identified during cloning of single HIV-specific B cells and designated 2C6, exhibited homology to mAb 47e, a known anti-CD4-induced coreceptor binding site antibody. The secreted monoclonal antibody 2C6 did not bind monomeric gp120, but specifically bound envelope on pseudovirions. A recombinant form of the antibody 2C6 acted as a CD4-induced epitope-specific antibody in neutralization assays, yet did not bind monomeric gp120. These findings imply specificity against a quaternary epitope presented on the pseudovirion envelope spike. These data demonstrate that Gag-Env pseudovirions recapitulate CD4 and coreceptor binding pocket antigenic structures and can facilitate identification of B-cell clones that secrete neutralizing antibodies.
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18 MeSH Terms
piggyBac transposon/transposase system to generate CD19-specific T cells for the treatment of B-lineage malignancies.
Manuri PV, Wilson MH, Maiti SN, Mi T, Singh H, Olivares S, Dawson MJ, Huls H, Lee DA, Rao PH, Kaminski JM, Nakazawa Y, Gottschalk S, Kebriaei P, Shpall EJ, Champlin RE, Cooper LJ
(2010) Hum Gene Ther 21: 427-37
MeSH Terms: Antigen-Presenting Cells, Antigens, CD19, Cell Line, Tumor, Cells, Cultured, Coculture Techniques, DNA Transposable Elements, Electroporation, Genetic Therapy, Genetic Vectors, Glioblastoma, Humans, K562 Cells, Lymphoma, B-Cell, Plasmids, Receptors, Antigen, T-Lymphocytes, Transgenes, Transposases
Show Abstract · Added August 22, 2013
Nonviral integrating vectors can be used for expression of therapeutic genes. piggyBac (PB), a transposon/transposase system, has been used to efficiently generate induced pluripotent stems cells from somatic cells, without genetic alteration. In this paper, we apply PB transposition to express a chimeric antigen receptor (CAR) in primary human T cells. We demonstrate that T cells electroporated to introduce the PB transposon and transposase stably express CD19-specific CAR and when cultured on CD19(+) artificial antigen-presenting cells, numerically expand in a CAR-dependent manner, display a phenotype associated with both memory and effector T cell populations, and exhibit CD19-dependent killing of tumor targets. Integration of the PB transposon expressing CAR was not associated with genotoxicity, based on chromosome analysis. PB transposition for generating human T cells with redirected specificity to a desired target such as CD19 is a new genetic approach with therapeutic implications.
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18 MeSH Terms
Evidence for preferential Ig gene usage and differential TdT and exonuclease activities in human naïve and memory B cells.
Tian C, Luskin GK, Dischert KM, Higginbotham JN, Shepherd BE, Crowe JE
(2007) Mol Immunol 44: 2173-83
MeSH Terms: Adult, Amino Acid Motifs, Animals, Antigens, CD19, B-Lymphocytes, Blood Donors, Cell Separation, Clone Cells, Complementarity Determining Regions, DNA Nucleotidylexotransferase, Exonucleases, Flow Cytometry, Gene Expression Regulation, Genes, Immunoglobulin, Humans, Immunoglobulin Heavy Chains, Immunoglobulin Isotypes, Immunoglobulin Variable Region, Immunologic Memory, Mice, Mutation, Nucleotides, Tumor Necrosis Factor Receptor Superfamily, Member 7
Show Abstract · Added August 6, 2012
Memory B cells and the antibodies they encode are important for protective immunity against infectious pathogens. Characterization of naïve and memory B cell antibody repertoires will elucidate the molecular basis for the generation of antibody diversity in human B cells and the optimization of antibody structures that bind microbial antigens. In this study we aimed to investigate the influence of antigenic selection on the antibody genes of the two CD27+ memory B cell subsets, comparing them with the naïve repertoire in CD27- cells. We analyzed and compared the Ig heavy chain gene transcripts in three recently defined circulating naïve and memory B cell subsets (CD19+IgD+CD27- [naïve], CD19+IgD+CD27+ [un-class-switched memory] or CD19+IgD- CD27+ [class-switched memory]) at the single cell level. We found similar biased patterns of variable, diversity and joining heavy chain gene usages in all three groups of cells. CD19+IgD+CD27+ memory B cells harbored as diverse an antibody gene repertoire as CD19+IgD-CD27+ memory B cells. Interestingly, CD19+IgD+CD27+ memory B cells possessed a lower frequency of somatic mutations, a higher incidence of exonuclease activity at the 3' end of D regions, and a lower frequency of N and P nucleotide additions at both VH-D and D-JH junctions of CDR3 regions compared to CD19+IgD-CD27+ memory B cells. These data suggest distinct functional mechanisms underlying selection of this unique subset of un-class-switched memory B cells.
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23 MeSH Terms
Global transcriptional coactivators CREB-binding protein and p300 are highly essential collectively but not individually in peripheral B cells.
Xu W, Fukuyama T, Ney PA, Wang D, Rehg J, Boyd K, van Deursen JM, Brindle PK
(2006) Blood 107: 4407-16
MeSH Terms: Alleles, Animals, Antigens, CD19, B-Lymphocytes, CREB-Binding Protein, Homeostasis, Integrases, Lymphocyte Count, Mice, p300-CBP Transcription Factors
Show Abstract · Added March 5, 2014
CREB-binding protein (CBP) and its para-log p300 are transcriptional coactivators that physically or functionally interact with over 320 mammalian and viral proteins, including 36 that are essential for B cells in mice. CBP and p300 are generally considered limiting for transcription, yet their roles in adult cell lineages are largely unknown since homozygous null mutations in either gene or compound heterozygosity cause early embryonic lethality in mice. We tested the hypotheses that CBP and p300 are limiting and that each has unique properties in B cells, by using mice with Cre/LoxP conditional knockout alleles for CBP (CBP(flox)) and p300 (p300(flox)), which carry CD19(Cre) that initiates floxed gene recombination at the pro-B-cell stage. CD19(Cre)-mediated loss of CBP or p300 led to surprisingly modest deficits in B-cell numbers, whereas inactivation of both genes was not tolerated by peripheral B cells. There was a moderate decrease in B-cell receptor (BCR)-responsive gene expression in CBP or p300 homozygous null B cells, suggesting that CBP and p300 are essential for this signaling pathway that is crucial for B-cell homeostasis. These results indicate that individually CBP and p300 are partially limiting beyond the pro-B-cell stage and that other coactivators in B cells cannot replace their combined loss.
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10 MeSH Terms