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1.
J Virol ; 87(24): 13904-10, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24089556

RESUMO

Epstein-Barr virus (EBV) is a vaccine/immunotherapy target due to its association with several human malignancies. EBNA-1 is an EBV protein consistently expressed in all EBV-associated cancers. Herein, EBNA-1-specific T cell epitopes were evaluated after AdC-rhEBNA-1 immunizations in chronically lymphocryptovirus-infected rhesus macaques, an EBV infection model. Preexisting rhEBNA-1-specific responses were augmented in 4/12 animals, and new epitopes were recognized in 5/12 animals after vaccinations. This study demonstrated that EBNA-1-specific T cells can be expanded by vaccination.


Assuntos
Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Infecções por Herpesviridae/veterinária , Lymphocryptovirus/imunologia , Macaca mulatta , Doenças dos Primatas/imunologia , Linfócitos T/imunologia , Animais , Mapeamento de Epitopos , Epitopos de Linfócito T/química , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/administração & dosagem , Antígenos Nucleares do Vírus Epstein-Barr/química , Antígenos Nucleares do Vírus Epstein-Barr/genética , Feminino , Infecções por Herpesviridae/tratamento farmacológico , Infecções por Herpesviridae/imunologia , Infecções por Herpesviridae/virologia , Lymphocryptovirus/genética , Macaca mulatta/genética , Macaca mulatta/imunologia , Macaca mulatta/virologia , Masculino , Doenças dos Primatas/tratamento farmacológico , Doenças dos Primatas/virologia , Linfócitos T/virologia , Vacinação , Vacinas Virais/administração & dosagem , Vacinas Virais/química , Vacinas Virais/genética , Vacinas Virais/imunologia
2.
Mol Ther Methods Clin Dev ; 32(1): 101186, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38282894

RESUMO

The use of lentiviral vectors in cell and gene therapy is steadily increasing, both in commercial and investigational therapies. Although existing data increasingly support the usefulness and safety of clinical-grade lentiviral vectors used in cell manufacturing, comprehensive studies specifically addressing their long-term stability are currently lacking. This is significant considering the high cost of producing and testing GMP-grade vectors, the limited number of production facilities, and lengthy queue for production slots. Therefore, an extended shelf life is a critical attribute to justify the investment in large vector lots for investigational cell therapies. This study offers a thorough examination of essential stability attributes, including vector titer, transduction efficiency, and potency for a series of clinical-grade vector lots, each assessed at a minimum of 36 months following their date of manufacture. The 13 vector lots included in this study were used for cell product manufacturing in 16 different clinical trials, and at the time of the analysis had a maximum storage time at -80°C of up to 8 years. The results emphasize the long-term durability and efficacy of GMP-grade lentiviral vectors for use in ex vivo cell therapy manufacturing.

3.
Nat Med ; 30(5): 1320-1329, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38480922

RESUMO

Recurrent glioblastoma (rGBM) remains a major unmet medical need, with a median overall survival of less than 1 year. Here we report the first six patients with rGBM treated in a phase 1 trial of intrathecally delivered bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). The study's primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints reported in this interim analysis include the frequency of manufacturing failures and objective radiographic response (ORR) according to modified Response Assessment in Neuro-Oncology criteria. All six patients had progressive, multifocal disease at the time of treatment. In both dose level 1 (1 ×107 cells; n = 3) and dose level 2 (2.5 × 107 cells; n = 3), administration of CART-EGFR-IL13Rα2 cells was associated with early-onset neurotoxicity, most consistent with immune effector cell-associated neurotoxicity syndrome (ICANS), and managed with high-dose dexamethasone and anakinra (anti-IL1R). One patient in dose level 2 experienced a dose-limiting toxicity (grade 3 anorexia, generalized muscle weakness and fatigue). Reductions in enhancement and tumor size at early magnetic resonance imaging timepoints were observed in all six patients; however, none met criteria for ORR. In exploratory endpoint analyses, substantial CAR T cell abundance and cytokine release in the cerebrospinal fluid were detected in all six patients. Taken together, these first-in-human data demonstrate the preliminary safety and bioactivity of CART-EGFR-IL13Rα2 cells in rGBM. An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time. ClinicalTrials.gov identifier: NCT05168423 .


Assuntos
Receptores ErbB , Glioblastoma , Imunoterapia Adotiva , Subunidade alfa2 de Receptor de Interleucina-13 , Receptores de Antígenos Quiméricos , Humanos , Glioblastoma/terapia , Glioblastoma/imunologia , Glioblastoma/diagnóstico por imagem , Glioblastoma/patologia , Subunidade alfa2 de Receptor de Interleucina-13/imunologia , Pessoa de Meia-Idade , Masculino , Receptores de Antígenos Quiméricos/imunologia , Feminino , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Adulto , Idoso , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patologia , Injeções Espinhais , Dose Máxima Tolerável
4.
Blood Cancer Discov ; 4(2): 118-133, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36413381

RESUMO

We conducted a phase I clinical trial of anti-BCMA chimeric antigen receptor T cells (CART-BCMA) with or without anti-CD19 CAR T cells (huCART19) in multiple myeloma (MM) patients responding to third- or later-line therapy (phase A, N = 10) or high-risk patients responding to first-line therapy (phase B, N = 20), followed by early lenalidomide or pomalidomide maintenance. We observed no high-grade cytokine release syndrome (CRS) and only one instance of low-grade neurologic toxicity. Among 15 subjects with measurable disease, 10 exhibited partial response (PR) or better; among 26 subjects responding to prior therapy, 9 improved their response category and 4 converted to minimal residual disease (MRD)-negative complete response/stringent complete response. Early maintenance therapy was safe, feasible, and coincided in some patients with CAR T-cell reexpansion and late-onset, durable clinical response. Outcomes with CART-BCMA + huCART19 were similar to CART-BCMA alone. Collectively, our results demonstrate favorable safety, pharmacokinetics, and antimyeloma activity of dual-target CAR T-cell therapy in early lines of MM treatment. SIGNIFICANCE: CAR T cells in early lines of MM therapy could be safer and more effective than in the advanced setting, where prior studies have focused. We evaluated the safety, pharmacokinetics, and efficacy of CAR T cells in patients with low disease burden, responding to current therapy, combined with standard maintenance therapy. This article is highlighted in the In This Issue feature, p. 101.


Assuntos
Mieloma Múltiplo , Receptores de Antígenos Quiméricos , Humanos , Mieloma Múltiplo/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Lenalidomida/uso terapêutico , Antígenos CD19/uso terapêutico , Linfócitos T
5.
Mol Ther ; 19(2): 417-26, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21081905

RESUMO

Despite enormous efforts by the scientific community, an effective HIV vaccine remains elusive. To further address to what degree T cells in absence of antibodies may protect against simian immunodeficiency virus (SIV) disease progression, rhesus macaques were vaccinated intramuscularly with a chimpanzee-derived Ad vector (AdC) serotype 6 and then boosted intramuscularly with a serologically distinct AdC vector of serotype 7 both expressing Gag of SIVmac239. Animals were subsequently boosted intramuscularly with a modified vaccinia Ankara (MVA) virus expressing Gag and Tat of the homologous SIV before mucosal challenge with a high dose of SIVmac239 given rectally. Whereas vaccinated animals showed only a modest reduction of viral loads, their overall survival was improved, in association with a substantial protection from the loss of CD4(+) T cells. In addition, the two vaccinated Mamu-A*01(+) macaques controlled viral loads to levels below detection within weeks after challenge. These data strongly suggest that T cells, while unable to affect SIV acquisition upon high-dose rectal infection, can reduce disease progression. Induction of potent T-cell responses should thus remain a component of our efforts to develop an efficacious vaccine to HIV-1.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Macaca mulatta/imunologia , Macaca mulatta/virologia , Vacinas contra a SAIDS/imunologia , Vírus da Imunodeficiência Símia/imunologia , Vírus da Imunodeficiência Símia/patogenicidade , Animais , Feminino , Masculino
6.
Expert Opin Biol Ther ; 15(6): 831-43, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25947115

RESUMO

INTRODUCTION: Advances in adoptive immunotherapy have enabled gene therapy approaches to be tested in clinical trials that involve the transfer of engineered immune cells to specifically target HIV-infected cells or block HIV infection or transmission. Genetic editing through engineered targeted nucleases provides a method for producing cells that are permanently resistant to HIV. AREAS COVERED: Here, we discuss current and developing gene therapy approaches aimed to confer resistance to HIV infection at the cellular level by targeting viral or cellular elements, with a focus on gene editing strategies that target viral entry. Human gene therapy trials in HIV infection are reviewed. EXPERT OPINION: In concept, a single infusion of genetically modified cells could potentially reduce the need for lifelong medication by providing long-term control over the virus (functional immunity). While the dream of completely eliminating viral reservoirs (sterilizing immunity) is appealing, this presents a significant additional hurdle and may not be necessary to improve long-term health. A single infusion, or a small number of infusions, of engineered cells may be shown in confirmatory clinical trials to produce a meaningful biologic effect. These techniques have implications for targeted gene therapy in HIV and other diseases.


Assuntos
Antirretrovirais , Terapia Genética/métodos , Infecções por HIV/genética , Infecções por HIV/terapia , Medicina de Precisão/métodos , Animais , Terapia Genética/tendências , Infecções por HIV/imunologia , HIV-1/genética , Humanos , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/tendências , Medicina de Precisão/tendências
7.
Mech Dev ; 130(4-5): 226-40, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23462683

RESUMO

The vertebrate axial skeleton (vertebral column and ribs) is derived from embryonic structures called somites. Mechanisms of somite formation and patterning are largely conserved along the length of the body axis, but segments acquire different morphologies in part through the action of Hox transcription factors. Although Hox genes' roles in axial skeletal patterning have been extensively characterized, it is still not well understood how they interact with somite patterning pathways to regulate different vertebral morphologies. Here, we investigated the role of Hoxa-5 in after somite segmentation in chick. Hoxa-5 mRNA is expressed in posterior cervical somites, and within them is restricted mainly to a sub-domain of lateral sclerotome. RNAi-based knockdown leads to cartilage defects in lateral vertebral elements (rib homologous structures) whose morphologies vary within and outside of the Hoxa-5 expression domain. Both knockdown and misexpression suggest that Hoxa-5 acts via negative regulation of Sox-9. Further, Hoxa-5 misexpression suggests that spatial and/or temporal restriction of Hoxa-5 expression is necessary for proper vertebral morphology. Finally, the restriction of Hoxa-5 expression to lateral sclerotome, which we hypothesize is important for its patterning function, involves regulation by signaling pathways that pattern somites, Fgf-8 and Shh.


Assuntos
Padronização Corporal , Vértebras Cervicais/embriologia , Vértebras Cervicais/patologia , Proteínas de Homeodomínio/metabolismo , Somitos/embriologia , Somitos/metabolismo , Animais , Biomarcadores/metabolismo , Cartilagem/embriologia , Cartilagem/metabolismo , Cartilagem/patologia , Embrião de Galinha , Galinhas , Condrócitos/metabolismo , Condrócitos/patologia , Condrogênese/genética , Fator 8 de Crescimento de Fibroblasto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Proteínas Hedgehog/metabolismo , Proteínas de Homeodomínio/genética , Fatores de Transcrição Box Pareados/metabolismo , Transporte Proteico , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição SOX9/metabolismo
8.
PLoS One ; 6(12): e28732, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22194898

RESUMO

"Day-7" myeloid DCs are commonly used in the clinic. However, there is a strong need to develop DCs faster that have the same potent immunostimulatory capacity as "Day-7" myeloid DCs and at the same time minimizing time, labor and cost of DC preparations. Although "2 days" DCs can elicit peptide-specific responses, they have not been demonstrated to engulf, process and present complex whole tumor lysates, which could be more convenient and personalized source of tumor antigens than defined peptides. In this preclinical study, we evaluated the T-cell stimulatory capacity of Day-2, Day-4, and Day-7 cultured monocyte-derived DCs loaded with SKOV3 cell whole lysate prepared by freeze-thaw or by UVB-irradiation followed by freeze-thaw, and matured with lipopolysaccharide (LPS) and interferon (IFN)-gamma. DCs were evaluated for antigen uptake, and following maturation with LPS and IFN-gamma, DCs were assessed for expression of CD80, CD40, CD86, ICAM-1 and CCR7, production of IL-12p70 and IP-10, and induction of tumor-specific T-cell responses. Day-4 and Day-7 DCs exhibited similar phagocytic abilities, which were superior to Day-2 DCs. Mature Day-7 DCs expressed the highest CD40 and ICAM-1, but mature Day-4 DCs produced the most IL-12p70 and IP-10. Importantly, Day-4 and Day-7 DCs derived from ovarian cancer patients stimulated equally strongly tumor-specific T-cell responses. This is the first study demonstrating the highly immunogenic and strong T-cell stimulatory properties of Day-4 myeloid DCs, and provided important preclinical data for rapid development of potent whole tumor lysate-loaded DC vaccines that are applicable to many tumor types.


Assuntos
Células Dendríticas/imunologia , Células Mieloides/imunologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Extratos de Tecidos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Apresentação Cruzada/efeitos dos fármacos , Citocinas/biossíntese , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Feminino , Saúde , Humanos , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Células Mieloides/citologia , Células Mieloides/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Fenótipo , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Doadores de Tecidos
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