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3.
Lancet Haematol ; 7(11): e816-e826, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33091355

RESUMO

BACKGROUND: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable activity in patients with refractory or relapsed acute lymphocytic leukaemia. Various anti-CD19 CAR T-cell constructs have been trialled and responses vary widely among different studies. We aimed to systematically analyse the outcomes of patients with acute lymphocytic leukaemia treated with anti-CD19 CAR T cells and identify factors associated with differences in outcomes. METHODS: We did a systematic review and meta-analysis of published and unpublished clinical trials that reported data on the outcomes of adult or paediatric patients that were treated with anti-CD19 CAR T cells for relapsed or refractory B-cell acute lymphocytic leukaemia, reported between Jan 1, 2012, and April 14, 2020. Studies with two patients or fewer were excluded and summary data were extracted from the reports. The primary outcome was the number of patients who had complete remission at any time after anti-CD19 CAR T-cell infusion. This study is not registered in PROSPERO. FINDINGS: From 1160 studies, we identified 40 potentially appropriate studies, 35 (88%) of which met the eligibility criteria and were included in the final analysis (n=953 patients). The pooled complete remission was 80% (95% CI 75·5-84·8) and heterogeneity between studies was moderate (I2=56·96%). In the prespecified subgroup analyses, 195 (75% [95% CI 66·9-82·9, I2=35·22%]) of 263 patients in adult studies and 242 (81% [72·9-87·2, I2=54·45%]) of 346 patients in paediatric studies achieved complete remission, p=0·24. The pooled complete remission did not significantly differ with anti-CD19 CAR T-cell construct type or single-chain variable fragment clone, but was higher with autologous T-cell origin (727 [83%, 78·5-86·5, I2=44·34%] of 901 patients), compared with allogeneic T-cell origin (29 [55%, 30·6-79·0, I2=62·64%] of 52 patients; p=0·018). 242 (26% [95% CI 18·5-34·1]) of 854 patients developed grade 3 or worse cytokine release syndrome and 97 (12% [6·6-19·2]) of 532 developed grade 3 or worse neurotoxicity. There was no difference in the proportion of patients who achieved complete remission or who had cytokine release syndrome or neurotoxicity between different anti-CD19 CAR T-cell constructs. The risk of bias was assessed as low in 17 studies and moderate in 18 studies. INTERPRETATION: The high response rates after anti-CD19 CAR T-cell therapy can be used to guide the use of therapy in patients with relapsed or refractory acute lymphocytic leukaemia. Comparison studies are required to further determine differences in efficacy between different anti-CD19 CAR T-cell constructs in the setting of relapsed or refractory acute lymphocytic leukaemia. FUNDING: National Cancer Institute, National Comprehensive Cancer Network, Mayo Clinic K2R Research Pipeline, and Mayo Clinic Center for Individualized Medicine.


Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Síndrome da Liberação de Citocina/etiologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Intervalo Livre de Progressão , Receptores de Antígenos Quiméricos/uso terapêutico , Indução de Remissão , Transplante Autólogo
5.
Scand J Immunol ; 92(4): e12917, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32557659

RESUMO

Ovarian Cancer (OC) is currently difficult to cure, mainly due to its late detection and the advanced state of the disease at the time of diagnosis. Therefore, conventional treatments such as debulking surgery and combination chemotherapy are rarely able to control progression of the tumour, and relapses are frequent. Alternative therapies are currently being evaluated, including immunotherapy and advanced T cell-based therapy. In the present review, we will focus on a description of those Chimeric Antigen Receptors (CARs) that have been validated in the laboratory or are being tested in the clinic. Numerous target antigens have been defined due to the identification of OC biomarkers, and many are being used as CAR targets. We provide an exhaustive list of these constructs and their current status. Despite being innovative and efficient, the OC-specific CARs face a barrier to their clinical efficacy: the tumour microenvironment (TME). Indeed, effector cells expressing CARs have been shown to be severely inhibited, rendering the CAR T cells useless once at the tumour site. Herein, we give a thorough description of the highly immunosuppressive OC TME and present recent studies and innovations that have enabled CAR T cells to counteract this negative environment and to destroy tumours.


Assuntos
Carcinoma Epitelial do Ovário/imunologia , Neoplasias Ovarianas/imunologia , Receptores de Antígenos Quiméricos/imunologia , Microambiente Tumoral/imunologia , Animais , Antígenos de Neoplasias/imunologia , Carcinoma Epitelial do Ovário/terapia , Feminino , Humanos , Imunoterapia Adotiva/métodos , Neoplasias Ovarianas/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Evasão Tumoral/imunologia
7.
Bull Cancer ; 107(7-8): 779-791, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32532420

RESUMO

Immunotherapy alone or in combination with chemotherapy is now an integral part of the treatment of metastatic NSCLC. This treatment is transforming the management of these cancers, with 20-30% of patients achieving long survival. However, disease progression under treatment is still the rule for the majority of patients, raising problems both in understanding its mechanisms and in subsequent appropriate management. This study examines current therapeutic options and proposes solutions to circumvent resistance to immunotherapy. The mechanisms of resistance to these treatments is also analysed.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia/métodos , Neoplasias Pulmonares/terapia , Quinase do Linfoma Anaplásico/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos Fase III como Assunto , Terapia Combinada/métodos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/fisiologia , Genes erbB-1 , Humanos , Imunoterapia Adotiva/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Mutação , Receptores de Antígenos Quiméricos/uso terapêutico , Translocação Genética
8.
Nat Rev Clin Oncol ; 17(7): 418-434, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32242094

RESUMO

Immuno-oncology approaches have entered clinical practice, with tremendous progress particularly in the field of T cell-engaging therapies over the past decade. Herein, we provide an overview of the current status of bispecific T cell engager (BiTE) therapy, considering the unprecedented new indication for such therapy in combating minimal (or measurable) residual disease in patients with acute lymphoblastic leukaemia, and the development of novel approaches based on this concept. Key aspects that we discuss include the current clinical data, challenges relating to treatment administration and patient monitoring, toxicities and resistance to treatment, and novel strategies to overcome these hurdles as well as to broaden the indications for BiTE therapy, particularly to common solid cancers. Elucidation of mechanisms of resistance and immune escape and new technologies used in drug development pave the way for new and more-effective therapies and rational combinatorial approaches. In particular, we highlight novel therapeutic agents, such as bifunctional checkpoint-inhibitory T cell engagers (CiTEs), simultaneous multiple interaction T cell engagers (SMITEs), trispecific killer engagers (TriKEs) and BiTE-expressing chimeric antigen receptor (CAR) T cells (CART.BiTE cells), designed to integrate various immune functions into one molecule or a single cellular vector and thereby enhance efficacy without compromising safety. We also discuss the targeting of intracellular tumour-associated epitopes using bispecific constructs with T cell receptor (TCR)-derived, rather than an antibody-based, antigen-recognition domains, termed immune-mobilizing monoclonal TCRs against cancer (ImmTACs), which might broaden the armamentarium of T cell-engaging therapies.


Assuntos
Imunoterapia Adotiva , Imunoterapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Anticorpos Biespecíficos/imunologia , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Linfócitos T/imunologia
9.
Medicine (Baltimore) ; 99(16): e19739, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32311967

RESUMO

RATIONALE: B cell lymphoma can co-occur with multiple myeloma (MM), and the prognosis in this case is usually poor. We propose the combination of CD19-chimeric antigen receptor (CAR) T cells and BCMA-CAR T cells for the treatment of such patients to obtain a superior prognosis. PATIENT CONCERNS: We present a 50-year-old patient with previous B cell lymphoma and subsequent multiple myeloma (MM). DIAGNOSIS: A diagnosis of B cell lymphoma and MM was made. INTERVENTIONS: The patient was treated with a combination of haploidentical CD19-chimeric antigen receptor (CAR) T cells and BCMA-CAR T cells. OUTCOMES: After CAR T cell therapy, the monoclonal plasma cells in the bone marrow and M protein disappeared. LESSONS: The combination therapy of CD19- and BCMA-CAR T cells is an effective measure to treat patients with concomitant or borderline cases of B cell lymphoma and MM.


Assuntos
Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B/terapia , Mieloma Múltiplo/terapia , Neoplasias Primárias Múltiplas , Segunda Neoplasia Primária , Receptores de Antígenos Quiméricos/uso terapêutico , Antineoplásicos/uso terapêutico , Feminino , Humanos , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Pessoa de Meia-Idade , Neoplasias Parotídeas/tratamento farmacológico
10.
Bull Cancer ; 107(2): 234-243, 2020 Feb.
Artigo em Francês | MEDLINE | ID: mdl-32035651

RESUMO

The approval of tisagenlecleucel in B-lineage acute lymphoblastic leukemias in 2017 in the USA and in 2018 in Europe not only opened new hopes but forced to rethink the hospital organizations around this innovation. Indeed, if these treatments are very effective in the short term, the complex logistics required imply high quality inter-center and intra-center collaboration. Hematology, intensive care unit, apheresis, neurology, cell therapy and biology laboratories, and radiology services must therefore act in a coordinated manner. A specialized monitoring for the mid and long term must also be implemented. Many questions remain concerning the profile of eligible patients, the short and long-term safety, the longer-term efficacy, improving the persistence of CAR-T cells, controlling the risk of tumor escape, the use of allogenic CAR-T cells, or the application of this concept to T-cell ALL. The precise evaluation of the involved costs and the cost-effectiveness of these therapies will also be the subject of future studies.


Assuntos
Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Humanos , Imunoterapia Adotiva/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Prognóstico , Receptores de Antígenos de Linfócitos T/uso terapêutico , Recidiva , Linfócitos T/efeitos dos fármacos
11.
Int J Mol Sci ; 21(2)2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31936170

RESUMO

Chimeric antigen receptors (CARs) have found clinical success in B cell malignancies, but a dearth of potential targets limits their wider clinical application, especially in solid tumours. Here, we describe the development of an anti-annexin A2 CAR, CAR(2448), derived from an antibody found to have activity against epithelial ovarian cancer cell lines. The spacer length of CAR(2448) was optimised based on in vitro cytotoxic activity against ovarian cancer (OC) cell lines via a real-time cytotoxicity assay. The longer spacer CAR(2448)L T cells exhibit significant effector activity, inducing inflammatory cytokine release and cytotoxicity against OC cell lines. Furthermore, CAR(2448)L-BBz T cells induced enhanced survival in an in vivo OC xenograft model and reduced tumour volume by 76.6%. Our preclinical studies of CAR(2448) suggest its potential for the unmet need of novel strategies for the treatment of ovarian cancer.


Assuntos
Anexina A2/imunologia , Carcinoma Epitelial do Ovário/terapia , Imunoterapia Adotiva , Neoplasias Ovarianas/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Animais , Anexina A2/antagonistas & inibidores , Carcinoma Epitelial do Ovário/imunologia , Linhagem Celular Tumoral , Feminino , Humanos , Imunoterapia Adotiva/métodos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Ovarianas/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
PLoS One ; 15(1): e0223814, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31910217

RESUMO

INTRODUCTION: Chimeric antigen receptor (CAR) T-cells have been recently developed and are producing impressive outcomes in patients with hematologic malignancies. However, there is no standardized method for cell trafficking and in vivo CAR T-cell monitoring. We assessed the feasibility of real-time in vivo 89Zr-p-Isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS, DFO) labeled CAR T-cell trafficking using positron emission tomography (PET). RESULTS: The 89Zr-DFO radiolabeling efficiency of Jurkat/CAR and human peripheral blood mononuclear cells (hPBMC)/CAR T-cells was 70%-79%, and cell radiolabeling activity was 98.1-103.6 kBq/106 cells. Cell viability after radiolabeling was >95%. Cell proliferation was not significantly different during the early period after radiolabeling, compared with unlabeled cells; however, the proliferative capacity decreased over time (day 7 after labeling). IL-2 or IFN-γ secretion was not significantly different between unlabeled and labeled CAR T-cells. PET/magnetic resonance imaging in the xenograft model showed that most of the 89Zr-DFO-labeled Jurkat/CAR T-cells were distributed in the lung (24.4% ± 3.4%ID) and liver (22.9% ± 5.6%ID) by one hour after injection. The cells gradually migrated from the lung to the liver and spleen by day 1, and remained stable in these sites until day 7 (on day 7: lung 3.9% ± 0.3%ID, liver 36.4% ± 2.7%ID, spleen 1.4% ± 0.3%ID). No significant accumulation of labeled cells was identified in tumors. A similar pattern was observed in ex vivo biodistributions on day 7 (lung 3.0% ± 1.0%ID, liver 19.8% ± 2.2%ID, spleen 2.3% ± 1.7%ID). 89Zr-DFO-labeled hPBMC/CAR T-cells showed a similar distribution, compared with Jurkat/CAR T-cells, on serial PET images. CAR T cell distribution was cross-confirmed by flow cytometry, Alu polymerase chain reaction, and immunohistochemistry. CONCLUSION: Real-time in vivo cell trafficking is feasible using PET imaging of 89Zr-DFO-labeled CAR T-cells. This can be used to investigate cellular kinetics, initial in vivo biodistribution, and safety profiles in future CAR T-cell development.


Assuntos
Desferroxamina/análogos & derivados , Isotiocianatos/farmacologia , Radioisótopos/farmacologia , Receptores de Antígenos de Linfócitos T/isolamento & purificação , Receptores de Antígenos Quiméricos/isolamento & purificação , Zircônio/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desferroxamina/farmacologia , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/patologia , Humanos , Imunoconjugados/farmacologia , Marcação por Isótopo , Células Jurkat , Leucócitos Mononucleares/química , Leucócitos Mononucleares/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Radioisótopos/química , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/química , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/química , Linfócitos T/imunologia , Distribuição Tecidual
14.
Hematol Oncol Stem Cell Ther ; 13(1): 1-6, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31202671

RESUMO

Advances in the fields of immuno-oncology and T-cell engineering have brought autologous chimeric antigen receptor T-cell (CART) therapies from the bench to the bedside. At present, two CART products that target CD19 are commercially available: tisagenlecleucel and axicabtagene ciloleucel. They have demonstrated remarkable efficacy for their particular indications. One challenge is to compare the safety among commercially available and clinical trial CART treatments due to the use of different grading models to assess the severity of cytokine release syndrome and neurotoxicity. An unmet need exists to harmonize current grading models in order to develop uniform treatment strategies to manage these toxicities. Here, we attempt to summarize the evolution of the various grading systems for cytokine release syndrome and neurotoxicity and also highlight the major differences among them, whenever applicable.


Assuntos
Síndrome da Liberação de Citocina/etiologia , Doenças do Sistema Nervoso/etiologia , Receptores de Antígenos Quiméricos/uso terapêutico , Síndrome da Liberação de Citocina/patologia , Humanos , Doenças do Sistema Nervoso/patologia
15.
Cancer Lett ; 472: 175-180, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31790761

RESUMO

Recently, the use of chimeric antigen receptor-modified T (CAR-T)-cells in the treatment of hematological tumors has been successful and has become a clinical hotspot in tumor immunotherapy. However, their wide application is limited by inherent risks such as graft-versus-host disease (GvHD) and the amount of time it takes to produce CAR-T cells. Natural killer (NK) cells can be xenografted and have the potential to become off-the-shelf products, making CAR-NK cell therapies universal products. These products may be safer than CAR-T cell therapy. Considering that the fundamental researche is still in its infancy, this review focuses on clinical achievements and new strategies for improving the safety and efficacy of CAR-NK cell therapy, as well as the corresponding challenges.


Assuntos
Neoplasias Hematológicas/terapia , Imunoterapia Adotiva , Imunoterapia , Receptores de Antígenos Quiméricos/uso terapêutico , Neoplasias Hematológicas/imunologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/transplante , Receptores de Antígenos Quiméricos/imunologia
16.
Nat Rev Clin Oncol ; 17(3): 147-167, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31848460

RESUMO

T cells genetically engineered to express chimeric antigen receptors (CARs) have proven - and impressive - therapeutic activity in patients with certain subtypes of B cell leukaemia or lymphoma, with promising efficacy also demonstrated in patients with multiple myeloma. Nevertheless, various barriers restrict the efficacy and/or prevent the widespread use of CAR T cell therapies in these patients as well as in those with other cancers, particularly solid tumours. Key challenges relating to CAR T cells include severe toxicities, restricted trafficking to, infiltration into and activation within tumours, suboptimal persistence in vivo, antigen escape and heterogeneity, and manufacturing issues. The evolution of CAR designs beyond the conventional structures will be necessary to address these limitations and to expand the use of CAR T cells to a wider range of malignancies. Investigators are addressing the current obstacles with a wide range of engineering strategies in order to improve the safety, efficacy and applicability of this therapeutic modality. In this Review, we discuss the innovative designs of novel CAR T cell products that are being developed to increase and expand the clinical benefits of these treatments in patients with diverse cancers.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Neoplasias/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/uso terapêutico , Engenharia Celular , Humanos , Linfoma/tratamento farmacológico , Linfoma/imunologia , Neoplasias/genética , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologia
17.
Nat Biomed Eng ; 4(2): 195-206, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31819155

RESUMO

Micropatterned nickel titanium (commonly known as nitinol) thin films with complex designs, high structural resolution and excellent biocompatibility can be cheaply fabricated using magnetron sputtering. Here, we show that these benefits can be leveraged to fabricate micromesh implants that are loaded with tumour-specific human chimeric antigen receptor (CAR)-T cells for the treatment of solid tumours. In a mouse model of non-resectable ovarian cancer, the cell-loaded nitinol thin films spatially conformed to the implantation site, fostered the rapid expansion of T cells, delivered a high density of T cells directly to the tumour and significantly improved animal survival. We also show that self-expandable stents that were coated with T-cell-loaded films and implanted into subcutaneous tumours in mice improved the duration of stent patency by delaying tumour ingrowth. By providing direct access to tumours, CAR-T-cell-loaded micropatterned nitinol thin films can improve the effects of cell-based therapies.


Assuntos
Ligas , Imunoterapia Adotiva/instrumentação , Imunoterapia Adotiva/métodos , Bombas de Infusão Implantáveis , Neoplasias Ovarianas/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Animais , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Camundongos , Neoplasias Ovarianas/imunologia , Linfócitos T/fisiologia
18.
O.F.I.L ; 30(4): 329-333, 2020.
Artigo em Espanhol | IBECS | ID: ibc-197508

RESUMO

La terapia celular adoptiva está revolucionando el panorama de la terapéutica actual. La gestión de los medicamentos CAR-T supone un reto para el sistema nacional de salud (SNS), pues se trata de medicamentos complejos de un elevado impacto sanitario. En esta línea, la elaboración de protocolos fármaco-clínicos con criterios claramente definidos ayudará a un correcto posicionamiento y selección de los pacientes candidatos a estas terapias. Así mismo, la administración de estos fármacos debe realizarse en centros previamente seleccionados y cualificados para tal fin, garantizando la equidad en el acceso. Por otro lado, es prioritario un abordaje multidisciplinar de todos los pacientes que sean tratados con las terapias CAR-T. Finalmente es fundamental la evaluación y el registro constante de resultados, los cuales contribuirán a determinar el beneficio real de la terapia, reclamando la necesidad de precios equitativos para garantizar la sostenibilidad del SNS y el acceso a los pacientes previamente seleccionados


Adoptive cell therapy is revolutionizing the current therapeutic landscape. The management of CAR-T drugs is a challenge for The National Health System (NHS), as they are complex drugs with high impact on health. This way, the development of clinical pharmaceutical protocols with clearly defined criteria, will help in correct positioning and selection of patients candidates for these therapies. Likewise, administration of these drugs must be carried out in centers previously selected and qualified for this purpose, guaranteeing equity of access. On the other hand, a multidisciplinary approach of all patients treated with CAR-T therapies is a priority. Finally, the assessment and the constant result recording are essencial, since they will contribute to determining the real benefit of these therapies, claiming the need for equitable prices, guaranteeing the sustainability of the NHS and the access of previously selected patients to them


Assuntos
Humanos , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/uso terapêutico , Legislação de Medicamentos , Receptores de Antígenos de Linfócitos T/uso terapêutico , Antígenos CD19/uso terapêutico , Avaliação de Medicamentos
19.
Front Immunol ; 10: 2664, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798590

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy is highly effective in the treatment of B-cell acute lymphoblastic leukemia (ALL) or B-cell lymphoma, providing alternative therapeutic options for patients who failed to respond to conventional treatment or relapse. Moreover, it can bridge other therapeutic strategies and greatly improve patient prognosis, with broad applicable prospects. Even so, 30-60% patients relapse after treatment, probably due to persistence of CAR T-cells and escape or downregulation of CD19 antigen, which is a great challenge for disease control. Therefore, understanding the mechanisms that underlie post-CAR relapse and establishing corresponding prevention and treatment strategies is important. Herein, we discuss post-CAR relapse from the aspects of CD19-positive and CD19-negative and provide some reasonable prevention and treatment strategies.


Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva/métodos , Recidiva Local de Neoplasia/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Humanos , Receptores de Antígenos Quiméricos/imunologia
20.
Front Immunol ; 10: 2683, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798595

RESUMO

Glioblastoma (GB) is the most common and aggressive primary brain tumor in adults and currently incurable. Despite multimodal treatment regimens, median survival in unselected patient cohorts is <1 year, and recurrence remains almost inevitable. Escape from immune surveillance is thought to contribute to the development and progression of GB. While GB tumors are frequently infiltrated by natural killer (NK) cells, these are actively suppressed by the GB cells and the GB tumor microenvironment. Nevertheless, ex vivo activation with cytokines can restore cytolytic activity of NK cells against GB, indicating that NK cells have potential for adoptive immunotherapy of GB if potent cytotoxicity can be maintained in vivo. NK cells contribute to cancer immune surveillance not only by their direct natural cytotoxicity which is triggered rapidly upon stimulation through germline-encoded cell surface receptors, but also by modulating T-cell mediated antitumor immune responses through maintaining the quality of dendritic cells and enhancing the presentation of tumor antigens. Furthermore, similar to T cells, specific recognition and elimination of cancer cells by NK cells can be markedly enhanced through expression of chimeric antigen receptors (CARs), which provides an opportunity to generate NK-cell therapeutics of defined specificity for cancer immunotherapy. Here, we discuss effects of the GB tumor microenvironment on NK-cell functionality, summarize early treatment attempts with ex vivo activated NK cells, and describe relevant CAR target antigens validated with CAR-T cells. We then outline preclinical approaches that employ CAR-NK cells for GB immunotherapy, and give an overview on the ongoing clinical development of ErbB2 (HER2)-specific CAR-NK cells currently applied in a phase I clinical trial in glioblastoma patients.


Assuntos
Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/transplante , Receptores de Antígenos Quiméricos/uso terapêutico , Animais , Humanos , Células Matadoras Naturais/imunologia , Receptores de Antígenos Quiméricos/imunologia
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