RESUMEN
Adoptive immunotherapy, or the infusion of lymphocytes, is a promising approach for the treatment of cancer and certain chronic viral infections. The application of the principles of synthetic biology to enhance T cell function has resulted in substantial increases in clinical efficacy. The primary challenge to the field is to identify tumor-specific targets to avoid off-tumor, on-target toxicity. Given recent advances in efficacy in numerous pilot trials, the next steps in clinical development will require multicenter trials to establish adoptive immunotherapy as a mainstream technology.
Asunto(s)
Inmunoterapia Adoptiva , Neoplasias/inmunología , Neoplasias/terapia , Virosis/inmunología , Virosis/terapia , Traslado Adoptivo , Animales , Antígenos/genética , Antígenos/inmunología , Biomarcadores , Tratamiento Basado en Trasplante de Células y Tejidos , Técnicas de Transferencia de Gen , Terapia Genética , Humanos , Neoplasias/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Transducción Genética , Virosis/genéticaRESUMEN
BACKGROUND: Significant advancements have been made in the field of cellular therapy as anti-cancer treatments, with the approval of chimeric antigen receptor (CAR)-T cell therapies and the development of other genetically engineered cellular therapies. CAR-T cell therapies have demonstrated remarkable clinical outcomes in various hematological malignancies, establishing their potential to change the current cancer treatment paradigm. Due to the increasing importance of genetically engineered cellular therapies in the oncology treatment landscape, implementing strategies to expedite development and evidence generation for the next generation of cellular therapy products can have a positive impact on patients. METHODS: We outline a risk-based methodology and assessment aid for the data extrapolation approach across related genetically engineered cellular therapy products. This systematic data extrapolation approach has applicability beyond CAR-T cells and can influence clinical development strategies for a variety of immune therapies such as T cell receptor (TCR) or genetically engineered and other cell-based therapies (e.g., tumor infiltrating lymphocytes, natural killer cells and macrophages). RESULTS: By analyzing commonalities in manufacturing processes, clinical trial designs, and regulatory considerations, key learnings were identified. These insights support optimization of the development and regulatory approval of novel cellular therapies. CONCLUSIONS: The field of cellular therapy holds immense promise in safely and effectively treating cancer. The ability to extrapolate data across related products presents opportunities to streamline the development process and accelerate the delivery of novel therapies to patients.
Asunto(s)
Ingeniería Genética , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Humanos , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Ingeniería Genética/métodos , Inmunoterapia Adoptiva/métodos , Neoplasias/terapia , Neoplasias/inmunología , Neoplasias/genética , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/inmunologíaRESUMEN
Cancer immunotherapy based on genetically redirecting T cells has been used successfully to treat B cell malignancies1-3. In this strategy, the T cell genome is modified by integration of viral vectors or transposons encoding chimaeric antigen receptors (CARs) that direct tumour cell killing. However, this approach is often limited by the extent of expansion and persistence of CAR T cells4,5. Here we report mechanistic insights from studies of a patient with chronic lymphocytic leukaemia treated with CAR T cells targeting the CD19 protein. Following infusion of CAR T cells, anti-tumour activity was evident in the peripheral blood, lymph nodes and bone marrow; this activity was accompanied by complete remission. Unexpectedly, at the peak of the response, 94% of CAR T cells originated from a single clone in which lentiviral vector-mediated insertion of the CAR transgene disrupted the methylcytosine dioxygenase TET2 gene. Further analysis revealed a hypomorphic mutation in this patient's second TET2 allele. TET2-disrupted CAR T cells exhibited an epigenetic profile consistent with altered T cell differentiation and, at the peak of expansion, displayed a central memory phenotype. Experimental knockdown of TET2 recapitulated the potency-enhancing effect of TET2 dysfunction in this patient's CAR T cells. These findings suggest that the progeny of a single CAR T cell induced leukaemia remission and that TET2 modification may be useful for improving immunotherapies.
Asunto(s)
5-Metilcitosina/metabolismo , Antígenos CD19/inmunología , Dioxigenasas/genética , Inmunoterapia/métodos , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/terapia , Linfocitos T/inmunología , Linfocitos T/trasplante , Traslado Adoptivo , Anciano , Alelos , Diferenciación Celular , Ensayos Clínicos como Asunto , Células Clonales/citología , Células Clonales/inmunología , Dioxigenasas/metabolismo , Epigénesis Genética , Células HEK293 , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Mutación , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Linfocitos T/citología , Linfocitos T/metabolismo , TransgenesRESUMEN
Adoptive T cell transfer for cancer and chronic infection is an emerging field that shows promise in recent trials. Synthetic-biology-based engineering of T lymphocytes to express high-affinity antigen receptors can overcome immune tolerance, which has been a major limitation of immunotherapy-based strategies. Advances in cell engineering and culture approaches to enable efficient gene transfer and ex vivo cell expansion have facilitated broader evaluation of this technology, moving adoptive transfer from a "boutique" application to the cusp of a mainstream technology. The major challenge currently facing the field is to increase the specificity of engineered T cells for tumors, because targeting shared antigens has the potential to lead to on-target off-tumor toxicities, as observed in recent trials. As the field of adoptive transfer technology matures, the major engineering challenge is the development of automated cell culture systems, so that the approach can extend beyond specialized academic centers and become widely available.
Asunto(s)
Inmunoterapia Adoptiva/métodos , Neoplasias/inmunología , Neoplasias/terapia , Linfocitos T/inmunología , Técnicas de Cultivo de Célula/métodos , Técnicas de Cultivo de Célula/tendencias , Humanos , Tolerancia Inmunológica/inmunología , Inmunoterapia Adoptiva/tendencias , Modelos Inmunológicos , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Biología Sintética/métodos , Biología Sintética/tendencias , Linfocitos T/metabolismo , Linfocitos T/trasplanteRESUMEN
The field of cell therapy is rapidly emerging as a priority area for oncology research and drug development. Currently, two chimeric antigen receptor T-cell therapies are approved by the US Food and Drug Administration and other agencies worldwide for two types of hematologic cancers. To facilitate the development of these therapies for patients with life-threatening cancers with limited or no therapeutic options, science- and risk-based approaches will be critical to mitigating and balancing any potential risk associated with either early clinical research or more flexible manufacturing paradigms. Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy convened an expert group of stakeholders to develop specific strategies and proposals for regulatory opportunities to accelerate the development of cell therapies as promising new therapeutics. This meeting took place in Washington, DC on May 17, 2019. As academia and industry expand research efforts and cellular product development pipelines, this report summarizes opportunities to accelerate entry into the clinic for exploratory studies and optimization of cell products through manufacturing improvements for these promising new therapies.
Asunto(s)
Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Inmunoterapia Adoptiva/métodos , Neoplasias/terapia , Terapias en Investigación/métodos , Niño , Terapia Combinada , Humanos , Neoplasias/inmunología , Padres , Seguridad del Paciente , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Immunotherapy, especially therapeutic vaccination, has a great deal of potential in the treatment of cancer and certain infectious diseases such as HIV (Allison et al., 2006; Fauci et al., 2008; Feldmann and Steinman, 2005). Numerous vaccine candidates have been tested in patients with a variety of tumor types and chronic viral diseases. Often, the best way to assess the clinical potential of these vaccines is to monitor the induced T cell response, and yet there are currently no standards for reporting these results. This letter is an effort to address this problem.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Inmunoensayo/normas , Monitorización Inmunológica/normas , Neoplasias/terapia , Guías de Práctica Clínica como Asunto/normas , Linfocitos T/inmunología , Vacunas Virales/uso terapéutico , Virosis/terapia , Vacunas contra el Cáncer/inmunología , Humanos , Inmunoterapia , Vacunas Virales/inmunologíaRESUMEN
Recent clinical success has underscored the potential for immunotherapy based on the adoptive cell transfer (ACT) of engineered T lymphocytes to mediate dramatic, potent, and durable clinical responses. This success has led to the broader evaluation of engineered T-lymphocyte-based adoptive cell therapy to treat a broad range of malignancies. In this review, we summarize concepts, successes, and challenges for the broader development of this promising field, focusing principally on lessons gleaned from immunological principles and clinical thought. We present ACT in the context of integrating T-cell and tumor biology and the broader systemic immune response.
Asunto(s)
Inmunoterapia Adoptiva , Neoplasias/inmunología , Neoplasias/terapia , Traslado Adoptivo/métodos , Animales , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Inmunoterapia Adoptiva/historia , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/tendencias , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
BACKGROUND: CCR5 is the major coreceptor for human immunodeficiency virus (HIV). We investigated whether site-specific modification of the gene ("gene editing")--in this case, the infusion of autologous CD4 T cells in which the CCR5 gene was rendered permanently dysfunctional by a zinc-finger nuclease (ZFN)--is safe. METHODS: We enrolled 12 patients in an open-label, nonrandomized, uncontrolled study of a single dose of ZFN-modified autologous CD4 T cells. The patients had chronic aviremic HIV infection while they were receiving highly active antiretroviral therapy. Six of them underwent an interruption in antiretroviral treatment 4 weeks after the infusion of 10 billion autologous CD4 T cells, 11 to 28% of which were genetically modified with the ZFN. The primary outcome was safety as assessed by treatment-related adverse events. Secondary outcomes included measures of immune reconstitution and HIV resistance. RESULTS: One serious adverse event was associated with infusion of the ZFN-modified autologous CD4 T cells and was attributed to a transfusion reaction. The median CD4 T-cell count was 1517 per cubic millimeter at week 1, a significant increase from the preinfusion count of 448 per cubic millimeter (P<0.001). The median concentration of CCR5-modified CD4 T cells at 1 week was 250 cells per cubic millimeter. This constituted 8.8% of circulating peripheral-blood mononuclear cells and 13.9% of circulating CD4 T cells. Modified cells had an estimated mean half-life of 48 weeks. During treatment interruption and the resultant viremia, the decline in circulating CCR5-modified cells (-1.81 cells per day) was significantly less than the decline in unmodified cells (-7.25 cells per day) (P=0.02). HIV RNA became undetectable in one of four patients who could be evaluated. The blood level of HIV DNA decreased in most patients. CONCLUSIONS: CCR5-modified autologous CD4 T-cell infusions are safe within the limits of this study. (Funded by the National Institute of Allergy and Infectious Diseases and others; ClinicalTrials.gov number, NCT00842634.).
Asunto(s)
Linfocitos T CD4-Positivos/trasplante , Terapia Genética , Infecciones por VIH/terapia , Transfusión de Linfocitos , Receptores CCR5/genética , Adulto , Terapia Antirretroviral Altamente Activa , Transfusión de Sangre Autóloga , Linfocitos T CD4-Positivos/química , Terapia Combinada , ADN Viral/sangre , Femenino , Terapia Genética/efectos adversos , Terapia Genética/métodos , VIH/genética , VIH/aislamiento & purificación , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , ARN Viral/sangre , Recto/inmunología , Carga ViralRESUMEN
Positive detection of minimal residual disease (MRD) by multichannel flow cytometry (MFC) prior to hematopoietic cell transplantation (HCT) of patients with acute lymphoblastic leukemia (ALL) identifies patients at high risk for relapse, but many pre-HCT MFC-MRD negative patients also relapse, and the predictive power MFC-MRD early post-HCT is poor. To test whether the increased sensitivity of next-generation sequencing (NGS)-MRD better identifies pre- and post-HCT relapse risk, we performed immunoglobulin heavy chain (IgH) variable, diversity, and joining (V[D]J) DNA sequences J NGS-MRD on 56 patients with B-cell ALL enrolled in Children's Oncology Group trial ASCT0431. NGS-MRD predicted relapse and survival more accurately than MFC-MRD (P < .0001), especially in the MRD negative cohort (relapse, 0% vs 16%; P = .02; 2-year overall survival, 96% vs 77%; P = .003). Post-HCT NGS-MRD detection was better at predicting relapse than MFC-MRD (P < .0001), especially early after HCT (day 30 MFC-MRD positive relapse rate, 35%; NGS-MRD positive relapse rate, 67%; P = .004). Any post-HCT NGS positivity resulted in an increase in relapse risk by multivariate analysis (hazard ratio, 7.7; P = .05). Absence of detectable IgH-V(D)J NGS-MRD pre-HCT defines good-risk patients potentially eligible for less intense treatment approaches. Post-HCT NGS-MRD is highly predictive of relapse and survival, suggesting a role for this technique in defining patients early who would be eligible for post-HCT interventions. The trial was registered at www.clinicaltrials.gov as #NCT00382109.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Cadenas Pesadas de Inmunoglobulina/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Exones VDJ/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Recurrencia , Factores de Riesgo , Trasplante Homólogo , Adulto JovenRESUMEN
Chimeric antigen receptor-modified T cells with specificity for CD19 have shown promise in the treatment of chronic lymphocytic leukemia (CLL). It remains to be established whether chimeric antigen receptor T cells have clinical activity in acute lymphoblastic leukemia (ALL). Two children with relapsed and refractory pre-B-cell ALL received infusions of T cells transduced with anti-CD19 antibody and a T-cell signaling molecule (CTL019 chimeric antigen receptor T cells), at a dose of 1.4×10(6) to 1.2×10(7) CTL019 cells per kilogram of body weight. In both patients, CTL019 T cells expanded to a level that was more than 1000 times as high as the initial engraftment level, and the cells were identified in bone marrow. In addition, the chimeric antigen receptor T cells were observed in the cerebrospinal fluid (CSF), where they persisted at high levels for at least 6 months. Eight grade 3 or 4 adverse events were noted. The cytokine-release syndrome and B-cell aplasia developed in both patients. In one child, the cytokine-release syndrome was severe; cytokine blockade with etanercept and tocilizumab was effective in reversing the syndrome and did not prevent expansion of chimeric antigen receptor T cells or reduce antileukemic efficacy. Complete remission was observed in both patients and is ongoing in one patient at 11 months after treatment. The other patient had a relapse, with blast cells that no longer expressed CD19, approximately 2 months after treatment. Chimeric antigen receptor-modified T cells are capable of killing even aggressive, treatment-refractory acute leukemia cells in vivo. The emergence of tumor cells that no longer express the target indicates a need to target other molecules in addition to CD19 in some patients with ALL.
Asunto(s)
Antígenos CD19 , Inmunoterapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfocitos T , Linfocitos T/inmunología , Niño , Quimera , Femenino , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Inducción de RemisiónRESUMEN
Many patients with acute myeloid leukemia (AML) are incurable with chemotherapy and may benefit from novel approaches. One such approach involves the transfer of T cells engineered to express chimeric antigen receptors (CARs) for a specific cell-surface antigen. This strategy depends upon preferential expression of the target on tumor cells. To date, the lack of AML-specific surface markers has impeded development of such CAR-based approaches. CD123, the transmembrane α chain of the interleukin-3 receptor, is expressed in the majority of AML cells but is also expressed in many normal hematopoietic cells. Here, we show that CD123 is a good target for AML-directed CAR therapy, because its expression increases over time in vivo even in initially CD123(dim) populations, and that human CD123-redirected T cells (CART123) eradicate primary AML in immunodeficient mice. CART123 also eradicated normal human myelopoiesis, a surprising finding because anti-CD123 antibody-based strategies have been reportedly well tolerated. Because AML is likely preceded by clonal evolution in "preleukemic" hematopoietic stem cells, our observations support CART123 as a viable AML therapy, suggest that CART123-based myeloablation may be used as a novel conditioning regimen for hematopoietic cell transplantation, and raise concerns for the use of CART123 without such a rescue strategy.
Asunto(s)
Antígenos de Neoplasias/inmunología , Inmunoterapia/métodos , Subunidad alfa del Receptor de Interleucina-3/inmunología , Leucemia Mieloide Aguda/inmunología , Linfocitos T/trasplante , Animales , Línea Celular Tumoral , Citometría de Flujo , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: Arthralgia is a common toxicity among women taking aromatase inhibitors (AIs) and can lead to premature discontinuation of therapy. We evaluated the association between arthralgia, co-morbid fatigue and/or insomnia, and inflammatory biomarkers among women taking AIs. METHODS: Women taking AIs for early-stage breast cancer completed a modified version of the Brief Pain Inventory, the Brief Fatigue Inventory, and the Insomnia Severity Index and provided blood samples for simultaneous assessment of 34 inflammatory biomarkers with a Luminex kit. Two-sided t tests were used to compare inflammatory biomarker concentrations for patients with or without moderate to severe arthralgia. Multivariate linear regression analyses were performed to evaluate the relationship between comorbid arthralgia, fatigue, and insomnia with identified biomarker concentrations. RESULTS: Among 203 participants, the severity of arthralgia, fatigue, and insomnia were significantly correlated with each other (p < 0.001 for all comparisons). After controlling for race, chemotherapy history, non-steroidal anti-inflammatory drug use, age, and body mass index, the coexistence of arthralgia, fatigue, and insomnia was associated with elevated C-reactive protein (CRP) (ß = 93.1; 95 % confidence interval (CI): 25.1-161.1; p = 0.008), eotaxin (ß = 79.9; 95 % CI: 32.5-127.2; p = 0.001), monocyte chemoattractant protein (MCP)-1 (ß = 151.2; 95 % CI: 32.7-269.8; p = 0.013), and vitamin D-binding protein (VDBP) (ß = 19,422; 95 % CI: 5500.5-33,344; p = 0.006). CONCLUSIONS: Among women taking AIs, the coexistence of arthralgia, fatigue, and insomnia was associated with increased levels of inflammatory biomarkers (elevated CRP, eotaxin, MCP-1, and VDBP). These findings suggest a possible shared inflammatory mechanism underlying these common symptoms.
Asunto(s)
Antineoplásicos Hormonales/efectos adversos , Inhibidores de la Aromatasa/efectos adversos , Artralgia/epidemiología , Artralgia/etiología , Neoplasias de la Mama/complicaciones , Anciano , Antineoplásicos Hormonales/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Biomarcadores , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Proteína C-Reactiva , Comorbilidad , Estudios Transversales , Fatiga/etiología , Femenino , Humanos , Mediadores de Inflamación/metabolismo , Persona de Mediana Edad , Estadificación de Neoplasias , Prevalencia , Trastornos del Inicio y del Mantenimiento del Sueño/etiologíaRESUMEN
Blinatumomab is a CD19/CD3-bispecific T-cell receptor-engaging (BiTE) antibody with efficacy in refractory B-precursor acute lymphoblastic leukemia. Some patients treated with blinatumomab and other T cell-activating therapies develop cytokine release syndrome (CRS). We hypothesized that patients with more severe toxicity may experience abnormal macrophage activation triggered by the release of cytokines by T-cell receptor-activated cytotoxic T cells engaged by BiTE antibodies and leading to hemophagocytic lymphohistiocytosis (HLH). We prospectively monitored a patient during blinatumomab treatment and observed that he developed HLH. He became ill 36 hours into the infusion with fever, respiratory failure, and circulatory collapse. He developed hyperferritinemia, cytopenias, hypofibrinogenemia, and a cytokine profile diagnostic for HLH. The HLH continued to progress after discontinuation of blinatumomab; however, he had rapid improvement after IL-6 receptor-directed therapy with tocilizumab. Patients treated with T cell-activating therapies, including blinatumomab, should be monitored for HLH, and cytokine-directed therapy may be considered in cases of life-threatening CRS. This trial was registered at www.clinicaltrials.gov as #NCT00103285.
Asunto(s)
Anticuerpos Biespecíficos/efectos adversos , Citocinas/metabolismo , Enfermedades del Sistema Inmune/inducido químicamente , Inmunoterapia/efectos adversos , Linfohistiocitosis Hemofagocítica/inducido químicamente , Activación de Macrófagos/inmunología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Linfocitos T Citotóxicos/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Niño , Síndrome de Down , Estudios de Seguimiento , Humanos , Enfermedades del Sistema Inmune/tratamiento farmacológico , Enfermedades del Sistema Inmune/inmunología , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfohistiocitosis Hemofagocítica/inmunología , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras B/inmunología , Estudios Prospectivos , Receptores de Interleucina-6/inmunología , Síndrome , Linfocitos T Citotóxicos/patología , Resultado del TratamientoRESUMEN
An obstacle to cancer immunotherapy has been that the affinity of T-cell receptors (TCRs) for antigens expressed in tumors is generally low. We initiated clinical testing of engineered T cells expressing an affinity-enhanced TCR against HLA-A*01-restricted MAGE-A3. Open-label protocols to test the TCRs for patients with myeloma and melanoma were initiated. The first two treated patients developed cardiogenic shock and died within a few days of T-cell infusion, events not predicted by preclinical studies of the high-affinity TCRs. Gross findings at autopsy revealed severe myocardial damage, and histopathological analysis revealed T-cell infiltration. No MAGE-A3 expression was detected in heart autopsy tissues. Robust proliferation of the engineered T cells in vivo was documented in both patients. A beating cardiomyocyte culture generated from induced pluripotent stem cells triggered T-cell killing, which was due to recognition of an unrelated peptide derived from the striated muscle-specific protein titin. These patients demonstrate that TCR-engineered T cells can have serious and not readily predictable off-target and organ-specific toxicities and highlight the need for improved methods to define the specificity of engineered TCRs.
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Enfermedades Cardiovasculares/complicaciones , Melanoma/sangre , Mieloma Múltiple/sangre , Proteínas Musculares/metabolismo , Miocardio/patología , Proteínas Quinasas/metabolismo , Linfocitos T/citología , Alelos , Secuencias de Aminoácidos , Antígenos de Neoplasias/metabolismo , Técnicas de Cultivo de Célula , Conectina , Citocinas/metabolismo , Epítopos/metabolismo , Antígenos HLA-A/metabolismo , Humanos , Inmunoterapia Adoptiva , Células Madre Pluripotentes Inducidas/citología , Masculino , Melanoma/terapia , Persona de Mediana Edad , Mieloma Múltiple/terapia , Miocardio/inmunología , Proteínas de Neoplasias/metabolismo , Péptidos/metabolismo , Ingeniería de Proteínas , Receptores de Antígenos de Linfocitos T/inmunologíaRESUMEN
We report the safety and tolerability of 87 infusions of lentiviral vectormodified autologous CD4 T cells (VRX496-T; trade name, Lexgenleucel-T) in 17 HIV patients with well-controlled viremia. Antiviral effects were studied during analytic treatment interruption in a subset of 13 patients. VRX496-T was associated with a decrease in viral load set points in 6 of 8 subjects (P = .08). In addition, A â G transitions were enriched in HIV sequences after infusion, which is consistent with a model in which transduced CD4 T cells exert antisense-mediated genetic pressure on HIV during infection. Engraftment of vector-modified CD4 T cells was measured in gut-associated lymphoid tissue and was correlated with engraftment in blood. The engraftment half-life in the blood was approximately 5 weeks, with stable persistence in some patients for up to 5 years. Conditional replication of VRX496 was detected periodically through 1 year after infusion. No evidence of clonal selection of lentiviral vectortransduced T cells or integration enrichment near oncogenes was detected. This is the first demonstration that gene-modified cells can exert genetic pressure on HIV. We conclude that gene-modified T cells have the potential to decrease the fitness of HIV-1 and conditionally replicative lentiviral vectors have a promising safety profile in T cells.
Asunto(s)
Linfocitos T CD4-Positivos/trasplante , Terapia Genética/métodos , Infecciones por VIH/terapia , VIH-1/genética , Lentivirus/genética , Oligonucleótidos Antisentido/farmacología , Traslado Adoptivo/métodos , Adulto , Antivirales/efectos adversos , Antivirales/metabolismo , Antivirales/farmacología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/fisiología , Femenino , Terapia Genética/efectos adversos , Vectores Genéticos/efectos adversos , Vectores Genéticos/metabolismo , Vectores Genéticos/farmacología , Infecciones por VIH/genética , Infecciones por VIH/inmunología , VIH-1/inmunología , Humanos , Lentivirus/metabolismo , Lentivirus/fisiología , Masculino , Persona de Mediana Edad , Oligonucleótidos/administración & dosificación , Oligonucleótidos/genética , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/efectos adversos , Oligonucleótidos Antisentido/genética , Transducción Genética/métodos , Carga Viral/efectos de los fármacos , Replicación Viral/genéticaRESUMEN
We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×10(5) cells per kilogram of body weight) of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect.
Asunto(s)
Antígenos CD19 , Inmunoterapia , Leucemia Linfoide/terapia , Receptores de Antígenos de Linfocitos T , Linfocitos T/inmunología , Agammaglobulinemia/etiología , Linfocitos B/inmunología , Médula Ósea/inmunología , Médula Ósea/patología , Quimera , Citocinas/sangre , Humanos , Inmunoterapia/efectos adversos , Lentivirus , Leucemia Linfoide/inmunología , Leucemia Linfoide/patología , Masculino , Receptores de Antígenos de Linfocitos T/genética , Inducción de Remisión , Síndrome de Lisis Tumoral/etiologíaRESUMEN
With this study we have demonstrated that in vitro transduction of normal human CD4(+) T lymphocytes with NPM-ALK results in their malignant transformation. The transformed cells become immortalized and display morphology and immunophenotype characteristic of patient-derived anaplastic large-cell lymphomas. These unique features, which are strictly dependent on NPM-ALK activity and expression, include perpetual cell growth, proliferation, and survival; activation of the key signal transduction pathways STAT3 and mTORC1; and expression of CD30 (the hallmark of anaplastic large-cell lymphoma) and of immunosuppressive cytokine IL-10 and cell-surface protein PD-L1/CD274. Implantation of NPM-ALK-transformed CD4(+) T lymphocytes into immunodeficient mice resulted in formation of tumors indistinguishable from patients' anaplastic large-cell lymphomas. Our findings demonstrate that the key aspects of human carcinogenesis closely recapitulating the features of the native tumors can be faithfully reproduced in vitro when an appropriate oncogene is used to transform its natural target cells; this in turn points to the fundamental role in malignant cell transformation of potent oncogenes expressed in the relevant target cells. Such transformed cells should permit study of the early stages of carcinogenesis, and in particular the initial oncogene-host cell interactions. This experimental design could also be useful for studies of the effects of early therapeutic intervention and likely also the mechanisms of malignant progression.
Asunto(s)
Linfocitos T CD4-Positivos , Transformación Celular Neoplásica , Regulación Neoplásica de la Expresión Génica/genética , Linfoma de Células B Grandes Difuso , Proteínas de Fusión Oncogénica/biosíntesis , Proteínas Tirosina Quinasas/biosíntesis , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Femenino , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Masculino , Ratones , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas/genética , Transducción de Señal/genéticaRESUMEN
NY-ESO-1 and LAGE-1 are cancer testis antigens with an ideal profile for tumor immunotherapy, combining up-regulation in many cancer types with highly restricted expression in normal tissues and sharing a common HLA-A*0201 epitope, 157-165. Here, we present data to describe the specificity and anti-tumor activity of a bifunctional ImmTAC, comprising a soluble, high-affinity T-cell receptor (TCR) specific for NY-ESO-1157-165 fused to an anti-CD3 scFv. This reagent, ImmTAC-NYE, is shown to kill HLA-A2, antigen-positive tumor cell lines, and freshly isolated HLA-A2- and LAGE-1-positive NSCLC cells. Employing time-domain optical imaging, we demonstrate in vivo targeting of fluorescently labelled high-affinity NYESO-specific TCRs to HLA-A2-, NY-ESO-1157-165-positive tumors in xenografted mice. In vivo ImmTAC-NYE efficacy was tested in a tumor model in which human lymphocytes were stably co-engrafted into NSG mice harboring tumor xenografts; efficacy was observed in both tumor prevention and established tumor models using a GFP fluorescence readout. Quantitative RT-PCR was used to analyze the expression of both NY-ESO-1 and LAGE-1 antigens in 15 normal tissues, 5 cancer cell lines, 10 NSCLC, and 10 ovarian cancer samples. Overall, LAGE-1 RNA was expressed at a greater frequency and at higher levels than NY-ESO-1 in the tumor samples. These data support the clinical utility of ImmTAC-NYE as an immunotherapeutic agent for a variety of cancers.
Asunto(s)
Antígenos de Neoplasias/inmunología , Antígenos de Superficie/inmunología , Proteínas de la Membrana/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Proteínas Recombinantes de Fusión/farmacología , Linfocitos T/inmunología , Animales , Anticuerpos Biespecíficos/inmunología , Anticuerpos Biespecíficos/farmacología , Antígenos de Neoplasias/biosíntesis , Antígenos de Superficie/biosíntesis , Complejo CD3/inmunología , Línea Celular Tumoral , Epítopos/inmunología , Femenino , Antígeno HLA-A2/inmunología , Humanos , Fragmentos de Inmunoglobulinas/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Melanoma/inmunología , Melanoma/metabolismo , Proteínas de la Membrana/biosíntesis , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/metabolismo , Distribución Aleatoria , Proteínas Recombinantes de Fusión/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
T-cell therapy represents an emerging and promising modality for the treatment of disease. Data from recent clinical trials of genetically modified T cells, most notably chimeric antigen receptor (CAR) T cells, have yielded dramatic clinical results and highlighted the potential for this approach to mediate anti-tumor activity. Continued progress in the development of such T-cell therapies will require the identification of the relevant biomarker strategies to support and guide clinical development of the candidate products. In this review, we review and discuss (i) principles for development and use of biomarkers in clinical research, (ii) the rationale and a strategy for the integration of biomarker data at all stages of the product development process, from preclinical studies through product manufacture and during the clinical trial and (iii) the different classes of biomarkers that are relevant to T-cell therapy trials. Throughout this review, we discuss how biomarkers can play a central role in the development of novel T-cell therapeutic agents and highlight how appropriately designed biomarker studies can provide critical insights to this process. Finally, we discuss future directions and challenges for the appropriate development of biomarkers to evaluate product bioactivity and treatment efficacy.
Asunto(s)
Tratamiento Basado en Trasplante de Células y Tejidos , Ensayos Clínicos como Asunto , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/citología , Biomarcadores/metabolismo , Investigación Biomédica , Humanos , Linfocitos T/metabolismoRESUMEN
A central role for T cells in the control of cancer has been supported by both animal models and clinical observations. Accordingly, the development of potent anti-tumor T cell immunity has been a long-standing objective of immunotherapy. Emerging data from clinical trials that test T cell immune-modulatory agents and genetically engineered and re-targeted T cells have begun to realize the profound potential of T cell immunotherapy to target cancer. This review will focus on a description of recent conceptual and technological advances for the genetic engineering of T cells to enhance anti-tumor T cell immunity through the introduction of tumor-specific receptors, both Chimeric Antigen Receptors (CAR) and T cell receptors (TcR), as well as an overview of emerging data from ongoing clinical trials that highlight the potential of these approaches to effect dramatic and potent anti-tumor immunity.