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1.
N Engl J Med ; 387(13): 1196-1206, 2022 09 29.
Artículo en Inglés | MEDLINE | ID: mdl-36170501

RESUMEN

BACKGROUND: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model. METHODS: In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy. RESULTS: A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×106 CAR T cells. At the 450×106 CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×106 to 150×106 cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×106 to 150×106 cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×106 to 150×106 cells. CONCLUSIONS: The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.).


Asunto(s)
Inmunoterapia Adoptiva , Mieloma Múltiple , Receptores Quiméricos de Antígenos , Receptores Acoplados a Proteínas G , Antígeno de Maduración de Linfocitos B/uso terapéutico , Síndrome de Liberación de Citoquinas/etiología , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/etiología , Receptores Quiméricos de Antígenos/uso terapéutico , Receptores Acoplados a Proteínas G/uso terapéutico , Linfocitos T
2.
Nature ; 568(7750): 112-116, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30918399

RESUMEN

Chimeric antigen receptors (CARs) are synthetic antigen receptors that reprogram T cell specificity, function and persistence1. Patient-derived CAR T cells have demonstrated remarkable efficacy against a range of B-cell malignancies1-3, and the results of early clinical trials suggest activity in multiple myeloma4. Despite high complete response rates, relapses occur in a large fraction of patients; some of these are antigen-negative and others are antigen-low1,2,4-9. Unlike the mechanisms that result in complete and permanent antigen loss6,8,9, those that lead to escape of antigen-low tumours remain unclear. Here, using mouse models of leukaemia, we show that CARs provoke reversible antigen loss through trogocytosis, an active process in which the target antigen is transferred to T cells, thereby decreasing target density on tumour cells and abating T cell activity by promoting fratricide T cell killing and T cell exhaustion. These mechanisms affect both CD28- and 4-1BB-based CARs, albeit differentially, depending on antigen density. These dynamic features can be offset by cooperative killing and combinatorial targeting to augment tumour responses to immunotherapy.


Asunto(s)
Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/metabolismo , Leucemia/inmunología , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Escape del Tumor/inmunología , Ligando 4-1BB/inmunología , Animales , Antígenos CD28/inmunología , Citotoxicidad Inmunológica , Femenino , Inmunoterapia Adoptiva , Leucemia/patología , Masculino , Ratones , Ratones Endogámicos NOD , Recurrencia Local de Neoplasia/inmunología , Linfocitos T/citología
3.
Mol Ther ; 31(3): 801-809, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-36518078

RESUMEN

The clinical impact of any therapy requires the product be safe and effective. Gammaretroviral vectors pose several unique risks, including inadvertent exposure to replication competent retrovirus (RCR) that can arise during vector manufacture. The US FDA has required patient monitoring for RCR, and the National Gene Vector Biorepository is an NIH resource that has assisted eligible investigators in meeting this requirement. To date, we have found no evidence of RCR in 338 pre-treatment and 1,595 post-treatment blood samples from 737 patients associated with 60 clinical trials. Most samples (75%) were obtained within 1 year of treatment, and samples as far out as 9 years after treatment were analyzed. The majority of trials (93%) were cancer immunotherapy, and 90% of the trials used vector products produced with the PG13 packaging cell line. The data presented here provide further evidence that current manufacturing methods generate RCR-free products and support the overall safety profile of retroviral gene therapy.


Asunto(s)
Retroviridae , Replicación Viral , Humanos , Retroviridae/genética , Vectores Genéticos/genética , Línea Celular , Terapia Genética/efectos adversos
4.
Blood ; 138(7): 531-543, 2021 08 19.
Artículo en Inglés | MEDLINE | ID: mdl-33851211

RESUMEN

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become a breakthrough treatment of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, despite the high initial response rate, the majority of adult patients with B-ALL progress after CD19 CAR T-cell therapy. Data on the natural history, management, and outcome of adult B-ALL progressing after CD19 CAR T cells have not been described in detail. Herein, we report comprehensive data of 38 adult patients with B-ALL who progressed after CD19 CAR T therapy at our institution. The median time to progression after CAR T-cell therapy was 5.5 months. Median survival after post-CAR T progression was 7.5 months. A high disease burden at the time of CAR T-cell infusion was significantly associated with risk of post-CAR T progression. Thirty patients (79%) received salvage treatment of post-CAR T disease progression, and 13 patients (43%) achieved complete remission (CR), but remission duration was short. Notably, 7 (58.3%) of 12 patients achieved CR after blinatumomab and/or inotuzumab administered following post-CAR T failure. Multivariate analysis revealed that a longer remission duration from CAR T cells was associated with superior survival after progression following CAR T-cell therapy. In summary, overall prognosis of adult B-ALL patients progressing after CD19 CAR T cells was poor, although a subset of patients achieved sustained remissions to salvage treatments, including blinatumomab, inotuzumab, and reinfusion of CAR T cells. Novel therapeutic strategies are needed to reduce risk of progression after CAR T-cell therapy and improve outcomes of these patients.


Asunto(s)
Anticuerpos Biespecíficos/administración & dosificación , Inmunoterapia Adoptiva , Inotuzumab Ozogamicina/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Terapia Recuperativa , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Tasa de Supervivencia
5.
Nature ; 545(7655): 423-431, 2017 05 24.
Artículo en Inglés | MEDLINE | ID: mdl-28541315

RESUMEN

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. Advances in the selection of optimal T cells, genetic engineering, and cell manufacturing are poised to broaden T-cell-based therapies and foster new applications in infectious diseases and autoimmunity.


Asunto(s)
Ingeniería Celular/métodos , Neoplasias/inmunología , Neoplasias/terapia , Linfocitos T/metabolismo , Linfocitos T/trasplante , Animales , Antígenos CD19/inmunología , Antígenos CD19/metabolismo , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Enfermedades Autoinmunes/terapia , Humanos , Infecciones/inmunología , Infecciones/patología , Infecciones/terapia , Neoplasias/patología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Proteínas Recombinantes de Fusión/inmunología , Proteínas Recombinantes de Fusión/metabolismo , Linfocitos T/inmunología , Microambiente Tumoral
6.
Eur J Immunol ; 51(9): 2151-2163, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34196410

RESUMEN

Spearheaded by the therapeutic use of chimeric antigen receptors (CARs) targeting CD19, synthetic immunology has entered the clinical arena. CARs are recombinant receptors for antigen that engage cell surface molecules through the variable region of an antibody and signal through arrayed T-cell activating and costimulatory domains. CARs allow redirection of T-cell cytotoxicity against any antigen of choice, independent of MHC expression. Patient T cells engineered to express CARs specific for CD19 have yielded remarkable outcomes in subjects with relapsed/refractory B- cell malignancies, setting off unprecedented interest in T-cell engineering and cell-based cancer immunotherapy. In this review, we present the challenges to extend the use of CAR T cells to solid tumors and other pathologies. We further highlight progress in CAR design, cell manufacturing, and genome editing, which in aggregate hold the promise of generating safer and more effective genetically instructed immunity. Novel engineered cell types, including innate T-cell types, natural killer (NK) cells, macrophages, and induced pluripotent stem cell-derived immune cells, are on the horizon, as are applications of CAR T cells to treat autoimmunity, severe infections, and senescence-associated pathologies.


Asunto(s)
Antígenos CD19/inmunología , Ingeniería Genética/métodos , Inmunoterapia Adoptiva/métodos , Leucemia de Células B/terapia , Receptores Quiméricos de Antígenos/inmunología , Enfermedades Autoinmunes/terapia , Ingeniería Celular/métodos , Edición Génica/métodos , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Asesinas Naturales/inmunología , Macrófagos/inmunología , Linfocitos T/inmunología , Linfocitos T/trasplante
7.
N Engl J Med ; 378(5): 449-459, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29385376

RESUMEN

BACKGROUND: CD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients. METHODS: We conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19-28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics. RESULTS: A total of 53 adults received 19-28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden. CONCLUSIONS: In the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19-28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069 .).


Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Receptores de Antígenos de Linfocitos T/uso terapéutico , Linfocitos T/inmunología , Adulto , Anciano , Citocinas/metabolismo , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Recurrencia , Inducción de Remisión , Análisis de Supervivencia
8.
Blood ; 134(7): 626-635, 2019 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-31262783

RESUMEN

High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or primary refractory (rel/ref) chemorefractory diffuse large B-cell lymphoma. Only 50% of patients are cured with this approach. We investigated safety and efficacy of CD19-specific chimeric antigen receptor (CAR) T cells administered following HDT-ASCT. Eligibility for this study includes poor-risk rel/ref aggressive B-cell non-Hodgkin lymphoma chemosensitive to salvage therapy with: (1) positron emission tomography-positive disease or (2) bone marrow involvement. Patients underwent standard HDT-ASCT followed by 19-28z CAR T cells on days +2 and +3. Of 15 subjects treated on study, dose-limiting toxicity was observed at both dose levels (5 × 106 and 1 × 107 19-28z CAR T per kilogram). Ten of 15 subjects experienced CAR T-cell-induced neurotoxicity and/or cytokine release syndrome (CRS), which were associated with greater CAR T-cell persistence (P = .05) but not peak CAR T-cell expansion. Serum interferon-γ elevation (P < .001) and possibly interleukin-10 (P = .07) were associated with toxicity. The 2-year progression-free survival (PFS) is 30% (95% confidence interval, 20% to 70%).  Subjects given decreased naive-like (CD45RA+CCR7+) CD4+ and CD8+ CAR T cells experienced superior PFS (P = .02 and .04, respectively). There was no association between CAR T-cell peak expansion, persistence, or cytokine changes and PFS. 19-28z CAR T cells following HDT-ASCT were associated with a high incidence of reversible neurotoxicity and CRS. Following HDT-ASCT, effector CD4+ and CD8+ immunophenotypes may improve disease control. This trial was registered at www.clinicaltrials.gov as #NCT01840566.


Asunto(s)
Inmunoterapia Adoptiva/métodos , Linfoma de Células B Grandes Difuso/terapia , Receptores de Antígenos de Linfocitos T/uso terapéutico , Trasplante de Células Madre/métodos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/terapia , Trasplante Autólogo/métodos , Resultado del Tratamiento
9.
Blood ; 134(26): 2361-2368, 2019 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-31650176

RESUMEN

Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high-dose (3 g/m2) cyclophosphamide (HD-Cy) for 17 patients and low-dose (≤1.5 g/m2) cyclophosphamide (LD-Cy) for 8 patients. Fifteen patients had pretreatment minimal residual disease (MRD; <5% blasts in bone marrow), and 10 patients had pretreatment morphologic evidence of disease (≥5% blasts in bone marrow). All toxicities were reversible, including severe cytokine release syndrome in 16% (4 of 25) and severe neurotoxicity in 28% (7 of 25) of patients. Treated patients were assessed for response, and, among the evaluable patients (n = 24), response and peak CAR T-cell expansion were superior in the HD-Cy/MRD cohorts, as compared with the LD-Cy/morphologic cohorts without an increase in toxicity. Our data support the safety of CD19-specific CAR T-cell therapy for R/R B-ALL. Our data also suggest that dose intensity of conditioning chemotherapy and minimal pretreatment disease burden have a positive impact on response without a negative effect on toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01860937.


Asunto(s)
Antígenos CD19/metabolismo , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Receptores Quiméricos de Antígenos/inmunología , Linfocitos T/trasplante , Adolescente , Adulto , Niño , Preescolar , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/patología , Síndrome de Liberación de Citoquinas/prevención & control , Femenino , Humanos , Lactante , Masculino , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/metabolismo , Neoplasia Residual/etiología , Neoplasia Residual/patología , Neoplasia Residual/prevención & control , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/prevención & control , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Terapia Recuperativa , Tasa de Supervivencia , Linfocitos T/inmunología , Resultado del Tratamiento , Adulto Joven
10.
Mol Ther ; 26(6): 1447-1456, 2018 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-29678657

RESUMEN

B cell maturation antigen (BCMA) has recently been identified as an important multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) T cell therapy. In CAR T cell therapy targeting CD19 for lymphoma, host immune anti-murine CAR responses limited the efficacy of repeat dosing and possibly long-term persistence. This clinically relevant concern can be addressed by generating a CAR incorporating a human single-chain variable fragment (scFv). We screened a human B cell-derived scFv phage display library and identified a panel of BCMA-specific clones from which human CARs were engineered. Despite a narrow range of affinity for BCMA, dramatic differences in CAR T cell expansion were observed between unique scFvs in a repeat antigen stimulation assay. These results were confirmed by screening in a MM xenograft model, where only the top preforming CARs from the repeat antigen stimulation assay eradicated disease and prolonged survival. The results of this screening identified a highly effective CAR T cell therapy with properties, including rapid in vivo expansion (>10,000-fold, day 6), eradication of large tumor burden, and durable protection to tumor re-challenge. We generated a bicistronic construct including a second-generation CAR and a truncated-epithelial growth factor receptor marker. CAR T cell vectors stemming from this work are under clinical investigation.


Asunto(s)
Antígeno de Maduración de Linfocitos B/metabolismo , Inmunoterapia Adoptiva/métodos , Anticuerpos de Cadena Única/inmunología , Inmunidad Adaptativa/fisiología , Linfocitos T CD4-Positivos/metabolismo , Herpesvirus Humano 4/inmunología , Humanos , Receptores de Antígenos de Linfocitos T/metabolismo
11.
Mol Ther ; 26(8): 1896-1905, 2018 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-29910179

RESUMEN

Patients with residual chronic lymphocytic leukemia (CLL) following initial purine analog-based chemoimmunotherapy exhibit a shorter duration of response and may benefit from novel therapeutic strategies. We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in patients with relapsed or refractory B cell acute lymphoblastic leukemia and CLL. Here we report the use of CD19-targeted CAR T cells incorporating the intracellular signaling domain of CD28 (19-28z) as a consolidative therapy in 8 patients with residual CLL following first-line chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab. Outpatients received low-dose conditioning therapy with cyclophosphamide (600 mg/m2), followed by escalating doses of 3 × 106, 1 × 107, or 3 × 107 19-28z CAR T cells/kg. An objective response was observed in 3 of 8 patients (38%), with a clinically complete response lasting more than 28 months observed in two patients. Self-limited fevers were observed post-CAR T cell infusion in 4 patients, contemporaneous with elevations in interleukin-6 (IL-6), IL-10, IL-2, and TGF-α. None developed severe cytokine release syndrome or neurotoxicity. CAR T cells were detectable post-infusion in 4 patients, with a longest observed persistence of 48 days by qPCR. Further strategies to enhance CAR T cell efficacy in CLL are under investigation.


Asunto(s)
Antígenos CD19/metabolismo , Ciclofosfamida/administración & dosificación , Inmunoterapia Adoptiva/efectos adversos , Leucemia Linfocítica Crónica de Células B/terapia , Linfocitos T/trasplante , Anciano , Terapia Conductista , Ciclofosfamida/uso terapéutico , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/inmunología , Masculino , Persona de Mediana Edad , Neoplasia Residual , Pentostatina/uso terapéutico , Rituximab/uso terapéutico , Linfocitos T/inmunología , Trasplante Autólogo/efectos adversos , Resultado del Tratamiento
12.
Mol Ther ; 25(5): 1117-1124, 2017 05 03.
Artículo en Inglés | MEDLINE | ID: mdl-28456379

RESUMEN

Chimeric antigen receptors (CARs) are synthetic receptors that reprogram T lymphocytes to target chosen antigens. The targeting of CD19, a cell surface molecule expressed in the vast majority of leukemias and lymphomas, has been successfully translated in the clinic, earning CAR therapy a special distinction in the selection of "cancer immunotherapy" by Science as the breakthrough of the year in 2013. CD19 CAR therapy is predicated on advances in genetic engineering, T cell biology, tumor immunology, synthetic biology, target identification, cell manufacturing sciences, and regulatory compliance-the central tenets of CAR therapy. Here, we review two of these foundations: the genetic engineering approaches and cell types to engineer.


Asunto(s)
Antígenos CD19/genética , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Leucemia/terapia , Linfoma/terapia , Proteínas Mutantes Quiméricas/genética , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T/inmunología , Antígenos CD19/inmunología , Ingeniería Celular/métodos , Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/inmunología , Humanos , Inmunoterapia/métodos , Lentivirus/genética , Lentivirus/inmunología , Leucemia/genética , Leucemia/inmunología , Leucemia/patología , Linfoma/genética , Linfoma/inmunología , Linfoma/patología , Proteínas Mutantes Quiméricas/inmunología , Ingeniería de Proteínas/métodos , Receptores de Antígenos de Linfocitos T/inmunología , Retroviridae/genética , Retroviridae/inmunología , Linfocitos T/clasificación , Linfocitos T/citología
13.
Blood ; 126(5): 616-9, 2015 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-26089395

RESUMEN

Globin gene therapy requires abundant numbers of highly engraftable, autologous hematopoietic stem cells expressing curative levels of ß-globin on differentiation. In this study, CD34+ cells from 31 thalassemic patients mobilized with hydroxyurea+granulocyte colony-stimulating factor (G-CSF), G-CSF, Plerixafor, or Plerixafor+G-CSF were transduced with the TNS9.3.55 ß-globin lentivector and compared for transducibility and globin expression in vitro, as well as engraftment potential in a xenogeneic model after partial myeloablation. Transduction efficiency and vector copy number (VCN) averaged 48.4 ± 2.8% and 1.91 ± 0.04, respectively, whereas expression approximated the one-copy normal ß-globin output. Plerixafor+G-CSF cells produced the highest ß-globin expression/VCN. Long-term multilineage engraftment and persistent VCN and vector expression was encountered in all xenografted groups, with Plerixafor+G-CSF-mobilized cells achieving superior short-term engraftment rates, with similar numbers of CD34+ cells transplanted. Overall, Plerixafor+G-CSF not only allows high CD34+ cell yields but also provides increased ß-globin expression/VCN and enhanced early human chimerism under nonmyeloablative conditions, thus representing an optimal graft for thalassemia gene therapy.


Asunto(s)
Terapia Genética/métodos , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas , Talasemia beta/terapia , Animales , Antígenos CD34/metabolismo , Bencilaminas , Ciclamas , Dosificación de Gen , Expresión Génica , Vectores Genéticos , Células Madre Hematopoyéticas/metabolismo , Compuestos Heterocíclicos/administración & dosificación , Xenoinjertos , Humanos , Ratones , Ratones Noqueados , Trasplante Autólogo , Globinas beta/genética , Talasemia beta/genética
14.
Blood ; 123(10): 1483-6, 2014 Mar 06.
Artículo en Inglés | MEDLINE | ID: mdl-24429337

RESUMEN

We conducted a pilot trial to investigate the safety and effectiveness of mobilizing CD34(+) hematopoietic progenitor cells (HPCs) in adults with ß-thalassemia major. We further assessed whether thalassemia patient CD34(+) HPCs could be transduced with a globin lentiviral vector under clinical conditions at levels sufficient for therapeutic implementation. All patients tolerated granulocyte colony-stimulating factor well with minimal side effects. All cell collections exceeded 8 × 10(6) CD34(+) cells/kg. Using clinical grade TNS9.3.55 vector, we demonstrated globin gene transfer averaging 0.53 in 3 validation runs performed under current good manufacturing practice conditions. Normalized to vector copy, the vector-encoded ß-chain was expressed at a level approximating normal hemizygous protein output. Importantly, stable vector copy number (0.2-0.6) and undiminished vector expression were obtained in NSG mice 6 months posttransplant. Thus, we validated a safe and effective procedure for ß-globin gene transfer in thalassemia patient CD34(+) HPCs, which we will implement in the first US trial in patients with severe inherited globin disorders. This trial is registered at www.clinicaltrials.gov as #NCT01639690.


Asunto(s)
Técnicas de Transferencia de Gen , Terapia Genética , Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas , Globinas beta/genética , Talasemia beta/genética , Talasemia beta/terapia , Animales , Antígenos CD34/metabolismo , Ensayo de Unidades Formadoras de Colonias , Modelos Animales de Enfermedad , Células Precursoras Eritroides/metabolismo , Expresión Génica , Vectores Genéticos/genética , Xenoinjertos , Humanos , Ratones , Transducción Genética , Globinas beta/biosíntesis , Talasemia beta/metabolismo
15.
Blood ; 119(5): 1107-16, 2012 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-22096239

RESUMEN

The genetic engineering of hematopoietic stem cells is the basis for potentially treating a large array of hereditary and acquired diseases, and stands as the paradigm for stem cell engineering in general. Recent clinical reports support the formidable promise of this approach but also highlight the limitations of the technologies used to date, which have on occasion resulted in clonal expansion, myelodysplasia, or leukemogenesis. New research directions, predicated on improved vector designs, targeted gene delivery or the therapeutic use of pluripotent stem cells, herald the advent of safer and more effective hematopoietic stem cell therapies that may transform medical practice. In this review, we place these recent advances in perspective, emphasizing the solutions emerging from a wave of new technologies and highlighting the challenges that lie ahead.


Asunto(s)
Ingeniería Celular/métodos , Células Madre Hematopoyéticas/citología , Marcación de Gen/métodos , Marcación de Gen/tendencias , Técnicas de Transferencia de Gen , Ingeniería Genética/métodos , Terapia Genética/métodos , Vectores Genéticos/genética , Vectores Genéticos/aislamiento & purificación , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Células Madre Hematopoyéticas/fisiología , Humanos , Modelos Biológicos , Retroviridae/genética , Retroviridae/aislamiento & purificación , Retroviridae/fisiología
16.
Res Sq ; 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-39011120

RESUMEN

We designed a CD19-targeted CAR comprising a calibrated signaling module, termed 1XX, that differs from that of conventional CD28/CD3z and 4-1BB/CD3z CARs. Here we report the first-in-human, phase 1 clinical trial of 19(T2)28z-1XX CAR T cells in relapsed/refractory large B-cell lymphoma. We hypothesized that 1XX CAR T cells may be effective at low doses and investigated 4 doubling dose levels starting from 25×106 CAR T cells. The overall response rate (ORR) was 82% and complete response (CR) rate 71% in the entire cohort (n=28) and 88% ORR and 75% CR in 16 patients treated at 25×106. With the median follow-up of 24 months, the 1-year EFS was 61% (95% CI: 45-82%). Overall, grade ≥3 CRS and ICANS rates were low at 4% and 7%. The calibrated potency of the 1XX CAR affords excellent efficacy at low cell doses and may benefit the treatment of other hematological malignancies, solid tumors and autoimmunity.

17.
Biochem Biophys Res Commun ; 438(1): 84-9, 2013 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-23872144

RESUMEN

Adoptive T-cell therapy with CD19-specific chimeric antigen receptors (CARs) is promising for treatment of advanced B-cell malignancies. Tumor targeting of CAR-modified T-cells is likely to contribute therapeutic potency; therefore we examined the relationship between the ability of CD19-specific CAR (CD19-CAR)-transduced T-cells to accumulate at CD19(+) tumor lesions, and their ability to provide anti-tumor effects in xenograft mouse models. Normal human peripheral blood lymphocytes, activated with immobilized RetroNectin and anti-CD3 antibodies, were transduced with retroviral vectors that encode CD19-CAR. Expanded CD19-CAR T-cells with a high transgene expression level of about 75% produced IL-2 and IFN-γ in response to CD19, and lysed both Raji and Daudi CD19(+) human B-cell lymphoma cell lines. Furthermore, these cells efficiently accumulated at Raji tumor lesions where they suppressed tumor progression and prolonged survival in tumor-bearing Rag2(-/-)γc(-/-) immunodeficient mice compared to control cohorts. These results show that the ability of CD19-CAR T-cells to home in on tumor lesions is pivotal for their anti-tumor effects in our xenograft models, and therefore may enhance the efficacy of adoptive T-cell therapy for refractory B-cell lymphoma.


Asunto(s)
Traslado Adoptivo/métodos , Antígenos CD19/inmunología , Linfoma de Células B/inmunología , Linfoma de Células B/patología , Linfocitos T/inmunología , Linfocitos T/patología , Animales , Antígenos CD19/genética , Línea Celular Tumoral , Humanos , Ratones , Ratones Endogámicos BALB C , Ingeniería de Proteínas/métodos
18.
Blood ; 118(18): 4817-28, 2011 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-21849486

RESUMEN

We report the findings from the first 10 patients with chemotherapy-refractory chronic lymphocytic leukemia (CLL) or relapsed B-cell acute lymphoblastic leukemia (ALL) we have enrolled for treatment with autologous T cells modified to express 19-28z, a second-generation chimeric antigen (Ag) receptor specific to the B-cell lineage Ag CD19. Eight of the 9 treated patients tolerated 19-28z(+) T-cell infusions well. Three of 4 evaluable patients with bulky CLL who received prior conditioning with cyclophosphamide exhibited either a significant reduction or a mixed response in lymphadenopathy without concomitant development of B-cell aplasia. In contrast, one patient with relapsed ALL who was treated in remission with a similar T-cell dose developed a predicted B-cell aplasia. The short-term persistence of infused T cells was enhanced by prior cyclophosphamide administration and inversely proportional to the peripheral blood tumor burden. Further analyses showed rapid trafficking of modified T cells to tumor and retained ex vivo cytotoxic potential of CD19-targeted T cells retrieved 8 days after infusion. We conclude that this adoptive T-cell approach is promising and more likely to show clinical benefit in the setting of prior conditioning chemotherapy and low tumor burden or minimal residual disease. These studies are registered at www.clinicaltrials.org as #NCT00466531 (CLL protocol) and #NCT01044069 (B-ALL protocol).


Asunto(s)
Antígenos CD19/inmunología , Supervivencia de Injerto , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Leucemia de Células B/terapia , Linfocitos T/trasplante , Adulto , Anciano , Antígenos CD19/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/fisiología , Femenino , Supervivencia de Injerto/fisiología , Humanos , Leucemia de Células B/tratamiento farmacológico , Leucemia de Células B/inmunología , Masculino , Persona de Mediana Edad , Recurrencia , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/fisiología , Trasplante Autólogo , Insuficiencia del Tratamiento
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