RESUMEN

Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 patients with medulloblastoma. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A*02+ DAOY cells as well as primary HLA-A*02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T-cell-related toxicity, an inducible caspase-9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically modified T cells. Altogether, these data indicate that T cells genetically modified with a high-affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating patients with HLA-A*02+ medulloblastoma.Significance: These findings identify PRAME as a medulloblastoma tumor-associated antigen that can be targeted using genetically modified T cells. Cancer Res; 78(12); 3337-49. ©2018 AACR.

Asunto(s)

Antígenos de Neoplasias/inmunología , Neoplasias Cerebelosas/terapia , Inmunoterapia Adoptiva/métodos , Meduloblastoma/terapia , Linfocitos T/trasplante , Adolescente , Animales , Antígenos de Neoplasias/metabolismo , Caspasa 9/genética , Caspasa 9/inmunología , Línea Celular Tumoral , Neoplasias Cerebelosas/inmunología , Neoplasias Cerebelosas/patología , Niño , Preescolar , Técnicas de Cocultivo , Estudios de Cohortes , Femenino , Genes Transgénicos Suicidas/genética , Genes Transgénicos Suicidas/inmunología , Antígeno HLA-A2/inmunología , Antígeno HLA-A2/metabolismo , Humanos , Masculino , Meduloblastoma/inmunología , Meduloblastoma/patología , Ratones , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

Therapeutic T cell engineering has recently garnered widespread interest because of the success of CD19 chimeric antigen receptor (CAR) therapy. CARs are synthetic receptors for antigen that redirect the specificity and reprogram the function of the T cells in which they are genetically introduced. CARs targeting CD19, a cell surface molecule found in most leukemias and lymphomas, have yielded high remission rates in patients with chemorefractory, relapsed disease, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. The toxicities of this treatment include B cell aplasia, cytokine release syndrome (CRS), and neurotoxicity. Although reversible in most instances, these toxicities may require specific medical interventions, including transfer to intensive care to treat severe CRS. Guidelines for managing these toxicities are emerging. The recent report of a nonhuman primate model for CRS is poised to help advance the management of this syndrome. Finally, new engineering modalities, based on the use of targeted nucleases like CRISPR, may further enhance the efficacy and safety of CAR T cells.

Asunto(s)

Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Inmunoterapia Adoptiva/métodos , Antígenos CD19/inmunología , Citocinas/efectos adversos , Citocinas/metabolismo , Edición Génica/métodos , Genes Transgénicos Suicidas/inmunología , Humanos , Inmunoterapia Adoptiva/efectos adversos , Leucemia/terapia , Linfoma/terapia , Enfermedades del Sistema Nervioso/etiología , Terapia Recuperativa/métodos

RESUMEN

In the case of disseminated cancer, current treatment options reach their limit. Gene theranostics emerge as an innovative route in the treatment and diagnosis of cancer and might pave the way towards development of an efficacious treatment of currently incurable cancer. Various gene vectors have been developed to realize tumor-specific nucleic acid delivery and are considered crucial for the successful application of cancer gene therapy. By adding reporter genes and imaging agents, these systems gain an additional diagnostic function, thereby advancing the theranostic paradigm into cancer gene therapy. Numerous preclinical studies have demonstrated the feasibility of combined tumor gene therapy and diagnostic imaging, and clinical trials in human and veterinary oncology have been executed with partly encouraging results.

Asunto(s)

Diagnóstico por Imagen/métodos , Terapia Genética/métodos , Oncología Médica/métodos , Neoplasias/tratamiento farmacológico , Citocinas/inmunología , Sistemas de Liberación de Medicamentos/métodos , Genes Reporteros , Genes Transgénicos Suicidas/inmunología , Vectores Genéticos/metabolismo , Humanos , Regiones Promotoras Genéticas

RESUMEN

PURPOSE OF REVIEW: In recent years, remarkable progress has been made in the development of cancer gene therapy into an applicable treatment modality for immunogene, suicide, gene correction and oncolytic therapies. New exciting developments for gene suppression or miRNA therapies are under way. The efforts are focused on more efficient and specific attack at known and novel targets, improvement of vector delivery and therapeutic efficacy. In this review, promising and new gene therapy approaches and clinical studies are briefly discussed to highlight important future directions of preclinical and clinical efforts. RECENT FINDINGS: Apart from progress for vector development and even more important, improvements for suicide, T-cell-based, oncolytic virus therapies were achieved. In addition, new emerging therapies are successfully developed, which are particularly promising for siRNA-based technologies applied to gene suppression therapy. Novel approaches, such as transcription factor ODN-based decoy, complement the spectrum of current cancer gene therapy. SUMMARY: In summary, cancer gene therapy has made remarkable progress in the improvement/refinement of existing strategies and delivery systems. The field is moving toward a therapeutic option, which will also be applicable for the treatment of disseminated metastases. Furthermore, numerous new approaches are about to be translated in clinical trials.

Asunto(s)

Diseño de Fármacos , Terapia Genética , MicroARNs/uso terapéutico , Neoplasias/terapia , Viroterapia Oncolítica , Factores de Transcripción/uso terapéutico , Vacunas de ADN , Apoptosis , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Reporteros/genética , Genes Reporteros/inmunología , Genes Transgénicos Suicidas/genética , Genes Transgénicos Suicidas/inmunología , Terapia Genética/tendencias , Humanos , Masculino , Neoplasias/genética , Neoplasias/inmunología , Viroterapia Oncolítica/tendencias , Factores de Transcripción/inmunología

RESUMEN

Allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)-haploidentical family donor (haplo-HSCT) is a readily available and potentially curative option for high-risk leukemia. In haplo-HSCT, alloreactivity plays a major role in the graft-versus-leukemia (GVL) effect, which, however, is frequently followed by relapse due to emerging leukemic cell variants that have lost the unshared HLA haplotype as a mechanism of immune escape. We report that stimulation of HLA-haploidentical donor T lymphocytes with leukemic antigen-presenting cells (L-APCs) expands a population of leukemia-reactive T cells, which, besides alloreactivity to unshared HLAs, contain leukemia-associated specificities restricted by shared HLAs. According to a preferential central-memory (T(CM)) phenotype and to high interleukin (IL)-7Rα expression, these T cells persist in vivo and sustain a major GVL effect in a clinically relevant xenograft model. Moreover, we demonstrate that modifying L-APC-expanded T cells to express the herpes simplex virus thymidine kinase (HSV-tk) suicide gene enables their elimination with the prodrug ganciclovir (GCV), therefore providing a safety switch in case of graft-versus-host disease (GVHD). These results warrant the clinical investigation of L-APC-expanded T cells modified with a suicide gene in the setting of haplo-HSCT.

Asunto(s)

Regulación Neoplásica de la Expresión Génica , Genes Transgénicos Suicidas/genética , Efecto Injerto vs Leucemia/genética , Antígenos HLA/genética , Leucemia/genética , Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Línea Celular Tumoral , Modelos Animales de Enfermedad , Citometría de Flujo , Ganciclovir/farmacología , Genes Transgénicos Suicidas/inmunología , Genes del Tumor de Wilms , Terapia Genética , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/terapia , Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Leucemia/patología , Leucemia/terapia , Ratones , Ratones SCID , Persona de Mediana Edad , Linfocitos T/trasplante , Adulto Joven

RESUMEN

In allogeneic hematopoietic cell transplantation (HSCT), donor T lymphocytes mediate the graft-versus-leukemia (GVL) effect, but induce graft-versus-host disease (GVHD). Suicide gene therapy-that is, the genetic induction of a conditional suicide phenotype into donor T cells-allows dissociating the GVL effect from GVHD. Genetic modification with retroviral vectors after CD3 activation reduces T-cell alloreactivity. We recently found that alloreactivity is maintained when CD28 costimulation, IL-7, and IL-15 are added. Herein, we used the minor histocompatibility (mH) antigens HA-1 and H-Y as model alloantigens to directly explore the antileukemia efficacy of human T cells modified with the prototypic suicide gene herpes simplex virus thymidine kinase (tk) after activation with different stimuli. Only in the case of CD28 costimulation, IL-7, and IL-15, the repertoire of tk(+) T cells contained HA-1- and H-Y-specific CD8(+) cytotoxic T cells (CTL) precursors. Thymidine kinase-positive HA-1- and H-Y-specific CTLs were capable of self-renewal and differentiation into potent antileukemia effectors in vitro, and in vivo in a humanized mouse model. Self-renewal and differentiation coincided with IL-7 receptor expression. These results pave the way to the clinical investigation of T cells modified with a suicide gene after CD28 costimulation, IL-7, and IL-15 for a safe and effective GVL effect.

Asunto(s)

Linfocitos T CD8-positivos/inmunología , Diferenciación Celular , Proliferación Celular , Genes Transgénicos Suicidas/inmunología , Leucemia/diagnóstico , Receptores de Interleucina-7/fisiología , Animales , Biomarcadores/metabolismo , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Femenino , Expresión Génica/fisiología , Terapia Genética/métodos , Vectores Genéticos/inmunología , Humanos , Inmunoterapia Adoptiva/métodos , Leucemia/genética , Leucemia/inmunología , Leucemia/terapia , Ratones , Ratones Endogámicos NOD , Ratones SCID , Pronóstico , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos T/genética , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Linfocitos T Citotóxicos/fisiología , Trasplante Homólogo

Asunto(s)

Terapia Genética/métodos , Neoplasias Pulmonares/terapia , Mesotelioma/terapia , Neoplasias Pleurales/terapia , Traslado Adoptivo/métodos , Animales , Apoptosis/genética , Apoptosis/inmunología , Vacunas contra el Cáncer/genética , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Ensayos Clínicos como Asunto , Citocinas/genética , Citocinas/inmunología , Genes Transgénicos Suicidas/genética , Genes Transgénicos Suicidas/inmunología , Genes Supresores de Tumor , Vectores Genéticos/genética , Vectores Genéticos/inmunología , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Mesotelioma/diagnóstico , Mesotelioma/genética , Mesotelioma/inmunología , Neoplasias Pleurales/diagnóstico , Neoplasias Pleurales/genética , Neoplasias Pleurales/inmunología , Pronóstico , ARN sin Sentido/genética , ARN sin Sentido/inmunología , Virus/genética

RESUMEN

Both malignant pleural mesothelioma and advanced stage lung cancer are associated with a poor prognosis. Unfortunately, current treatment regimens have had only a modest effect on their progressive course. Gene therapy for thoracic malignancies represents a novel therapeutic approach and has been evaluated in a number of clinical trials over the last two decades. Using viral vectors or anti-sense RNA, strategies have included induction of apoptosis, tumor suppressor gene replacement, suicide gene expression, cytokine-based therapy, various vaccination approaches, and adoptive transfer of modified immune cells. This review will consider the clinical results, limitations, and future directions of gene therapy trials for thoracic malignancies.

Asunto(s)

Terapia Genética/métodos , Neoplasias Pulmonares/terapia , Mesotelioma/terapia , Neoplasias Pleurales/terapia , Traslado Adoptivo/métodos , Animales , Apoptosis/genética , Apoptosis/inmunología , Vacunas contra el Cáncer/genética , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Ensayos Clínicos como Asunto , Citocinas/genética , Citocinas/inmunología , Genes Transgénicos Suicidas/genética , Genes Transgénicos Suicidas/inmunología , Genes Supresores de Tumor , Vectores Genéticos/genética , Vectores Genéticos/inmunología , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Mesotelioma/diagnóstico , Mesotelioma/genética , Mesotelioma/inmunología , Neoplasias Pleurales/diagnóstico , Neoplasias Pleurales/genética , Neoplasias Pleurales/inmunología , Pronóstico , ARN sin Sentido/genética , ARN sin Sentido/inmunología , Virus/genética

RESUMEN

We have completed a phase I/II suicide gene therapy clinical trial in patients with prostate cancer, using an E1/E3-deleted replication-deficient adenovirus (CTL102) encoding the bacterial nitroreductase enzyme in combination with prodrug CB1954. This study has provided an opportunity to monitor and characterize vector- and tumor-specific adaptive immunity before and after single or repeat injections of adenovirus. Here we report robust vector-specific humoral and cellular immune responses in all patients monitored. However, we found no correlation between preexisting immunity or the magnitude of the immune response to vector and the clinical outcome as measured by changes in serum prostate-specific antigen (PSA) level. Increased frequency of T cells recognizing prostate-specific antigens PSA or prostate-specific membrane antigen (PSMA) was detected in 3 of 11 patients after therapy, suggesting that this direct cytotoxic strategy can also stimulate tumor-specific immunity.

Asunto(s)

Aziridinas/uso terapéutico , Genes Transgénicos Suicidas/genética , Terapia Genética/métodos , Vectores Genéticos/inmunología , Profármacos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/terapia , Adenoviridae , Ensayo de Inmunoadsorción Enzimática , Genes Transgénicos Suicidas/inmunología , Humanos , Interferón gamma/inmunología , Masculino , Nitrorreductasas , Antígeno Prostático Específico/sangre , Antígeno Prostático Específico/inmunología , Neoplasias de la Próstata/inmunología , Linfocitos T/inmunología

RESUMEN

Suicide gene therapy has been used for the treatment of a variety of cancers. We reported previously the in vitro efficacy of the Herpes Simplex Virus Thymidine kinase (HSV-tk)/ganciclovir (GCV) system to mediate cytotoxicity in oral squamous cancer cells, using transferrin (Tf)-lipoplexes, prepared from cationic liposomes composed of 1,2-dioleoyl-3-(trimethylammonium) propane (DOTAP) and cholesterol. In the present study, we evaluated the antitumoral efficacy mediated by this lipoplex formulation in two suicide gene therapy strategies, HSV-tk/GCV and cytosine deaminase (CD)/5-fluorocytosine (5-FC), using a syngeneic, orthotopic murine model for head and neck squamous cell carcinoma. The cellular and molecular events associated with the antitumoral response elicited by both the therapeutic approaches were investigated by analyzing tumor cell death, tumor-infiltrating immune cells and tumor cytokine microenvironment. Significant tumor reduction was achieved upon intratumoral delivery of HSV-tk or CD genes mediated by Tf-lipoplexes, followed by intraperitoneal injection of GCV or 5-FC, respectively. Enhanced apoptosis, the recruitment of NK cells, CD4 and CD8 T-lymphocytes and an increase in the levels of several cytokines/chemokines were observed within the tumors. These observations suggest that suicide gene therapy with lipoplexes modifies the tumor microenvironment, and leads to the recruitment of immune effector cells that can act as adjuvants in reducing the tumor size.

Asunto(s)

Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/terapia , Técnicas de Transferencia de Gen , Genes Transgénicos Suicidas/inmunología , Terapia Genética , Neoplasias de la Boca/inmunología , Neoplasias de la Boca/terapia , Simplexvirus/inmunología , Timidina Quinasa/inmunología , Animales , Antimetabolitos/farmacología , Antivirales/farmacología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Apoptosis/inmunología , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/genética , Colesterol/química , Colesterol/farmacología , Citocinas/inmunología , Ácidos Grasos Monoinsaturados/química , Ácidos Grasos Monoinsaturados/farmacología , Femenino , Flucitosina/farmacología , Ganciclovir/farmacología , Genes Transgénicos Suicidas/genética , Liposomas/química , Liposomas/farmacocinética , Linfocitos/inmunología , Ratones , Neoplasias de la Boca/enzimología , Neoplasias de la Boca/genética , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/farmacología , Simplexvirus/enzimología , Simplexvirus/genética , Timidina Quinasa/genética , Transferrina , Proteínas Virales/genética

RESUMEN

Long-term clinical remissions of leukemia, after allogeneic hematopoietic stem cell transplantation, depend on alloreactive memory T cells able to self-renew and differentiate into antileukemia effectors. This is counterbalanced by detrimental graft-versus-host disease (GVHD). Induction of a selective suicide in donor T cells is a current gene therapy approach to abrogate GVHD. Unfortunately, genetic modification reduces alloreactivity of lymphocytes. This associates with an effector memory (T(EM)) phenotype of gene-modified lymphocytes and may limit antileukemia effect. We hypothesized that alloreactivity of gene-modified lymphocytes segregates with the central memory (T(CM)) phenotype. To this, we generated suicide gene-modified T(CM) lymphocytes with a retroviral vector after CD28 costimulation and culture with IL-2, IL-7, or a combination of IL-7 and IL-15. In vitro, suicide gene-modified T(CM) cells self-renewed upon alloantigen stimulation and resisted activation-induced cell death. In a humanized mouse model, only suicide gene-modified T cells cultured with IL-7 and IL-15 persisted, differentiated in T(EM) cells, and were as potent as unmanipulated lymphocytes in causing GVHD. GVHD was halted through the activation of the suicide gene machinery. These results warrant the use of suicide gene-modified T(CM) cells cultured with IL-7 and IL-15 for the safe exploitation of the alloreactive response against cancer.

Asunto(s)

Genes Transgénicos Suicidas/inmunología , Enfermedad Injerto contra Huésped/inmunología , Memoria Inmunológica , Interleucina-15/farmacología , Interleucina-7/farmacología , Trasplante de Células Madre , Linfocitos T/inmunología , Animales , Muerte Celular/genética , Muerte Celular/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Genes Transgénicos Suicidas/genética , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/terapia , Humanos , Memoria Inmunológica/genética , Interleucina-15/inmunología , Interleucina-2/genética , Interleucina-2/inmunología , Interleucina-7/inmunología , Isoantígenos/genética , Isoantígenos/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/terapia

RESUMEN

In allogeneic hematopoietic cell transplantation (allo-HCT), the immune recognition of host antigens by donor T lymphocytes leads to a beneficial graft-versus-leukemia (GvL) effect as well as to life-threatening graft-versus-host disease (GvHD). Genetic modification of T lymphocytes with a retroviral vector (RV) expressing the herpes simplex virus-thymidine kinase (TK) suicide gene confers selective sensitivity to the prodrug ganciclovir (GCV). In patients, the infusion of TK+ lymphocytes and the subsequent administration of GCV resulted in a time-wise modulation of antihost reactivity for a GvL effect, while controlling GvHD. Because activation required for genetic modification with RV may reduce antihost reactivity, we investigated the requirements for maximizing the potency of human TK+ lymphocytes. Whereas T-cell receptor triggering alone led to effector memory (EM) TK+ lymphocytes, the addition of CD28 costimulation through cell-sized beads resulted in the generation of central memory (CM) TK+ lymphocytes. In a quantitative model for GvHD using nonobese diabetic/severely combined immunodeficient mice, CM TK+ lymphocytes were more potent than EM TK+ lymphocytes. GCV administration efficiently controlled GvHD induced by CM TK+ lymphocytes. These results warrant the clinical investigation of CM suicide gene-modified human T lymphocytes for safe and effective allo-HCT.

Asunto(s)

Genes Transgénicos Suicidas/inmunología , Terapia Genética , Enfermedad Injerto contra Huésped/terapia , Retroviridae , Linfocitos T/inmunología , Timidina Quinasa/inmunología , Proteínas Virales/inmunología , Animales , Antivirales/administración & dosificación , Antígenos CD28/inmunología , Femenino , Ganciclovir/administración & dosificación , Genes Transgénicos Suicidas/genética , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunología , Efecto Injerto vs Leucemia/genética , Efecto Injerto vs Leucemia/inmunología , Trasplante de Células Madre Hematopoyéticas , Humanos , Memoria Inmunológica , Ratones , Ratones Endogámicos NOD , Ratones SCID , Receptores de Antígenos de Linfocitos T/inmunología , Simplexvirus/genética , Simplexvirus/inmunología , Linfocitos T/trasplante , Timidina Quinasa/genética , Trasplante Homólogo , Proteínas Virales/genética

RESUMEN

Suicide gene therapy is one approach being evaluated for the control of graft-vs-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). We recently constructed a novel chimeric suicide gene in which the entire coding region of HSV thymidine kinase (HSV-tk) was fused in-frame to the extracellular and transmembrane domains of human CD34 (DeltaCD34-tk). DeltaCD34-tk is an attractive candidate as a suicide gene in man because of the ensured expression of HSV-tk in all selected cells and the ability to rapidly and efficiently purify gene-modified cells using clinically approved CD34 immunoselection techniques. In this study we assessed the efficacy of the DeltaCD34-tk suicide gene in the absence of extended ex vivo manipulation by generating transgenic animals that express DeltaCD34-tk in the peripheral and thymic T cell compartments using the CD2 locus control region. We found that DeltaCD34-tk-expressing T cells could be purified to near homogeneity by CD34 immunoselection and selectively eliminated ex vivo and in vivo when exposed to low concentrations of GCV. The optimal time to administer GCV after allogeneic BMT with DeltaCD34-tk-expressing transgenic T cells was dependent on the intensity of the conditioning regimen, the leukemic status of the recipient, and the dose and timing of T cell infusion. Importantly, we used a controlled graft-vs-host reaction to promote alloengraftment in sublethally irradiated mice and provide a graft-vs-leukemia effect in recipients administered a delayed infusion of DeltaCD34-tk-expressing T cells. This murine model demonstrates the potential usefulness of DeltaCD34-tk-expressing T cells to control GVHD, promote alloengraftment, and provide a graft-vs-leukemia effect in man.

Asunto(s)

Antígenos CD34/genética , Trasplante de Médula Ósea/inmunología , Genes Transgénicos Suicidas/inmunología , Supervivencia de Injerto/inmunología , Enfermedad Injerto contra Huésped/inmunología , Efecto Injerto vs Leucemia/inmunología , Subgrupos de Linfocitos T/trasplante , Timidina Quinasa/genética , Animales , Antígenos CD34/biosíntesis , Antígenos CD34/inmunología , Trasplante de Médula Ósea/patología , Muerte Celular/genética , Muerte Celular/inmunología , Línea Celular Tumoral , Esquema de Medicación , Ganciclovir/administración & dosificación , Ganciclovir/efectos adversos , Ganciclovir/uso terapéutico , Supervivencia de Injerto/efectos de los fármacos , Supervivencia de Injerto/genética , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Efecto Injerto vs Leucemia/genética , Humanos , Cinética , Transfusión de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Quimera por Radiación/inmunología , Simplexvirus/enzimología , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/enzimología , Subgrupos de Linfocitos T/patología , Timidina Quinasa/biosíntesis , Timidina Quinasa/inmunología , Acondicionamiento Pretrasplante/efectos adversos

RESUMEN

Cytomegalovirus (CMV) is responsible for significant morbidity and mortality in immunocompromised patients undergoing allogeneic hematopoietic stem cell transplantation. The limitations of antiviral drugs and a better understanding of the cellular immune response to CMV has lead to the development of alternative therapies that restore host cellular immunity to CMV. Infusion of donor T lymphocytes results in variable protection against CMV but a high incidence of graft-versus-host disease in the allogeneic setting. To prevent this complication and further improve anti-CMV immune response, several groups have developed new approaches, such as the introduction of a suicide gene to control alloreactivity against the host or the selective activation of CMV-specific T cells by antigen-presenting cells expressing CMV antigens introduced by gene transfer. Depending on the target cells and the strategy chosen, adenovirus, retrovirus or poxviruses derived vectors are used for gene transfer. The protocols as well as the preclinical and clinical results obtained in the field of anti-CMV immunotherapy using gene transfer are reported and discussed.

Asunto(s)

Infecciones por Citomegalovirus/terapia , Terapia Genética/métodos , Inmunoterapia/métodos , Linfocitos T/inmunología , Células Presentadoras de Antígenos/inmunología , Antígenos Virales/genética , Antígenos Virales/inmunología , Linfocitos B/inmunología , Linfocitos B/virología , Citomegalovirus/genética , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/prevención & control , Células Dendríticas/inmunología , Genes Transgénicos Suicidas/inmunología , Vectores Genéticos/genética , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/terapia , Herpesvirus Humano 4/genética , Humanos , Huésped Inmunocomprometido/inmunología , Leucocitos Mononucleares/inmunología , Fosfoproteínas/genética , Fosfoproteínas/inmunología , Linfocitos T Citotóxicos/inmunología , Timidina Quinasa/genética , Transfección , Vacunación , Proteínas de la Matriz Viral/genética , Proteínas de la Matriz Viral/inmunología

Asunto(s)

Efecto Espectador/inmunología , Genes Transgénicos Suicidas/inmunología , Terapia Genética/métodos , Neoplasias/inmunología , Profármacos/farmacocinética , Animales , Biotransformación , Enzimas/genética , Flucitosina/farmacocinética , Flucitosina/toxicidad , Ganciclovir/farmacocinética , Ganciclovir/toxicidad , Humanos , Profármacos/uso terapéutico , Simplexvirus/enzimología , Linfocitos T/inmunología , Timidina Quinasa/genética