RESUMO
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.
Assuntos
Antígenos de Neoplasias/imunologia , Neoplasias Cerebelares/terapia , Imunoterapia Adotiva/métodos , Meduloblastoma/terapia , Linfócitos T/transplante , Adolescente , Animais , Antígenos de Neoplasias/metabolismo , Caspase 9/genética , Caspase 9/imunologia , Linhagem Celular Tumoral , Neoplasias Cerebelares/imunologia , Neoplasias Cerebelares/patologia , Criança , Pré-Escolar , Técnicas de Cocultura , Estudos de Coortes , Feminino , Genes Transgênicos Suicidas/genética , Genes Transgênicos Suicidas/imunologia , Antígeno HLA-A2/imunologia , Antígeno HLA-A2/metabolismo , Humanos , Masculino , Meduloblastoma/imunologia , Meduloblastoma/patologia , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Imunoterapia Adotiva/métodos , Antígenos CD19/imunologia , Citocinas/efeitos adversos , Citocinas/metabolismo , Edição de Genes/métodos , Genes Transgênicos Suicidas/imunologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Leucemia/terapia , Linfoma/terapia , Doenças do Sistema Nervoso/etiologia , Terapia de Salvação/métodosRESUMO
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.
Assuntos
Diagnóstico por Imagem/métodos , Terapia Genética/métodos , Oncologia/métodos , Neoplasias/tratamento farmacológico , Citocinas/imunologia , Sistemas de Liberação de Medicamentos/métodos , Genes Reporter , Genes Transgênicos Suicidas/imunologia , Vetores Genéticos/metabolismo , Humanos , Regiões Promotoras GenéticasRESUMO
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.
Assuntos
Desenho de Fármacos , Terapia Genética , MicroRNAs/uso terapêutico , Neoplasias/terapia , Terapia Viral Oncolítica , Fatores de Transcrição/uso terapêutico , Vacinas de DNA , Apoptose , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Reporter/genética , Genes Reporter/imunologia , Genes Transgênicos Suicidas/genética , Genes Transgênicos Suicidas/imunologia , Terapia Genética/tendências , Humanos , Masculino , Neoplasias/genética , Neoplasias/imunologia , Terapia Viral Oncolítica/tendências , Fatores de Transcrição/imunologiaRESUMO
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.
Assuntos
Regulação Neoplásica da Expressão Gênica , Genes Transgênicos Suicidas/genética , Efeito Enxerto vs Leucemia/genética , Antígenos HLA/genética , Leucemia/genética , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Citometria de Fluxo , Ganciclovir/farmacologia , Genes Transgênicos Suicidas/imunologia , Genes do Tumor de Wilms , Terapia Genética , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/terapia , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia/patologia , Leucemia/terapia , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Linfócitos T/transplante , Adulto JovemRESUMO
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.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Proliferação de Células , Genes Transgênicos Suicidas/imunologia , Leucemia/diagnóstico , Receptores de Interleucina-7/fisiologia , Animais , Biomarcadores/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Feminino , Expressão Gênica/fisiologia , Terapia Genética/métodos , Vetores Genéticos/imunologia , Humanos , Imunoterapia Adotiva/métodos , Leucemia/genética , Leucemia/imunologia , Leucemia/terapia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Prognóstico , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T/genética , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/fisiologia , Transplante HomólogoAssuntos
Terapia Genética/métodos , Neoplasias Pulmonares/terapia , Mesotelioma/terapia , Neoplasias Pleurais/terapia , Transferência Adotiva/métodos , Animais , Apoptose/genética , Apoptose/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Ensaios Clínicos como Assunto , Citocinas/genética , Citocinas/imunologia , Genes Transgênicos Suicidas/genética , Genes Transgênicos Suicidas/imunologia , Genes Supressores de Tumor , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Mesotelioma/diagnóstico , Mesotelioma/genética , Mesotelioma/imunologia , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/genética , Neoplasias Pleurais/imunologia , Prognóstico , RNA Antissenso/genética , RNA Antissenso/imunologia , Vírus/genéticaRESUMO
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.
Assuntos
Terapia Genética/métodos , Neoplasias Pulmonares/terapia , Mesotelioma/terapia , Neoplasias Pleurais/terapia , Transferência Adotiva/métodos , Animais , Apoptose/genética , Apoptose/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Ensaios Clínicos como Assunto , Citocinas/genética , Citocinas/imunologia , Genes Transgênicos Suicidas/genética , Genes Transgênicos Suicidas/imunologia , Genes Supressores de Tumor , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Mesotelioma/diagnóstico , Mesotelioma/genética , Mesotelioma/imunologia , Neoplasias Pleurais/diagnóstico , Neoplasias Pleurais/genética , Neoplasias Pleurais/imunologia , Prognóstico , RNA Antissenso/genética , RNA Antissenso/imunologia , Vírus/genéticaRESUMO
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.
Assuntos
Aziridinas/uso terapêutico , Genes Transgênicos Suicidas/genética , Terapia Genética/métodos , Vetores Genéticos/imunologia , Pró-Fármacos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/terapia , Adenoviridae , Ensaio de Imunoadsorção Enzimática , Genes Transgênicos Suicidas/imunologia , Humanos , Interferon gama/imunologia , Masculino , Nitrorredutases , Antígeno Prostático Específico/sangue , Antígeno Prostático Específico/imunologia , Neoplasias da Próstata/imunologia , Linfócitos T/imunologiaRESUMO
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.
Assuntos
Genes Transgênicos Suicidas/imunologia , Doença Enxerto-Hospedeiro/imunologia , Memória Imunológica , Interleucina-15/farmacologia , Interleucina-7/farmacologia , Transplante de Células-Tronco , Linfócitos T/imunologia , Animais , Morte Celular/genética , Morte Celular/imunologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Genes Transgênicos Suicidas/genética , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/terapia , Humanos , Memória Imunológica/genética , Interleucina-15/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-7/imunologia , Isoantígenos/genética , Isoantígenos/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/terapiaRESUMO
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.
Assuntos
Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/terapia , Técnicas de Transferência de Genes , Genes Transgênicos Suicidas/imunologia , Terapia Genética , Neoplasias Bucais/imunologia , Neoplasias Bucais/terapia , Simplexvirus/imunologia , Timidina Quinase/imunologia , Animais , Antimetabólitos/farmacologia , Antivirais/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Apoptose/imunologia , Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/genética , Colesterol/química , Colesterol/farmacologia , Citocinas/imunologia , Ácidos Graxos Monoinsaturados/química , Ácidos Graxos Monoinsaturados/farmacologia , Feminino , Flucitosina/farmacologia , Ganciclovir/farmacologia , Genes Transgênicos Suicidas/genética , Lipossomos/química , Lipossomos/farmacocinética , Linfócitos/imunologia , Camundongos , Neoplasias Bucais/enzimologia , Neoplasias Bucais/genética , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Simplexvirus/enzimologia , Simplexvirus/genética , Timidina Quinase/genética , Transferrina , Proteínas Virais/genéticaRESUMO
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.
Assuntos
Genes Transgênicos Suicidas/imunologia , Terapia Genética , Doença Enxerto-Hospedeiro/terapia , Retroviridae , Linfócitos T/imunologia , Timidina Quinase/imunologia , Proteínas Virais/imunologia , Animais , Antivirais/administração & dosagem , Antígenos CD28/imunologia , Feminino , Ganciclovir/administração & dosagem , Genes Transgênicos Suicidas/genética , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Efeito Enxerto vs Leucemia/genética , Efeito Enxerto vs Leucemia/imunologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Memória Imunológica , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptores de Antígenos de Linfócitos T/imunologia , Simplexvirus/genética , Simplexvirus/imunologia , Linfócitos T/transplante , Timidina Quinase/genética , Transplante Homólogo , Proteínas Virais/genéticaRESUMO
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.
Assuntos
Antígenos CD34/genética , Transplante de Medula Óssea/imunologia , Genes Transgênicos Suicidas/imunologia , Sobrevivência de Enxerto/imunologia , Doença Enxerto-Hospedeiro/imunologia , Efeito Enxerto vs Leucemia/imunologia , Subpopulações de Linfócitos T/transplante , Timidina Quinase/genética , Animais , Antígenos CD34/biossíntese , Antígenos CD34/imunologia , Transplante de Medula Óssea/patologia , Morte Celular/genética , Morte Celular/imunologia , Linhagem Celular Tumoral , Esquema de Medicação , Ganciclovir/administração & dosagem , Ganciclovir/efeitos adversos , Ganciclovir/uso terapêutico , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/genética , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Efeito Enxerto vs Leucemia/genética , Humanos , Cinética , Transfusão de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Quimera por Radiação/imunologia , Simplexvirus/enzimologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/enzimologia , Subpopulações de Linfócitos T/patologia , Timidina Quinase/biossíntese , Timidina Quinase/imunologia , Condicionamento Pré-Transplante/efeitos adversosRESUMO
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.