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1.
N Engl J Med ; 382(6): 545-553, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-32023374

RESUMO

BACKGROUND: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations. METHODS: In this phase 1 and 2 trial, we administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19-positive cancers (non-Hodgkin's lymphoma or chronic lymphocytic leukemia [CLL]). NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1×105, 1×106, or 1×107 CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy. RESULTS: The administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. The maximum tolerated dose was not reached. Of the 11 patients who were treated, 8 (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter's transformation component but had persistent CLL. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months. CONCLUSIONS: Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects. (Funded by the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot and the National Institutes of Health; ClinicalTrials.gov number, NCT03056339.).


Assuntos
Antígenos CD19 , Células Matadoras Naturais/transplante , Leucemia Linfocítica Crônica de Células B/terapia , Linfoma não Hodgkin/terapia , Receptores de Antígenos Quiméricos/antagonistas & inibidores , Idoso , Aloenxertos , Terapia Baseada em Transplante de Células e Tecidos , Feminino , Sangue Fetal , Vetores Genéticos , Humanos , Células Matadoras Naturais/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Linfoma não Hodgkin/imunologia , Masculino , Pessoa de Meia-Idade , Indução de Remissão/métodos , Retroviridae/genética , Condicionamento Pré-Transplante
2.
Bull Cancer ; 106(11): 946-958, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31711572

RESUMO

AIM: A HER2-specific second-generation chimeric antigen receptor (5.137.z) was introduced into NK-92 cells, designated as NK-92/5.137.z cells. To evaluate the function and effectiveness of NK-92/5.137.z cells against gastric cancer cells and further determined whether combination with apatinib can synergize with this NK cell-based practice to better suppress gastric cancer. METHODS: The expression of HER2 was examined in gastric cancer. The in vitro and in vivo cytotoxic activities of NK-92/5.137.z cells with or without apatinib were evaluated against gastric cancer cell lines. RESULTS: HER2 proteins were over-expressed in a considerable proportion of gastric cancer cells. NK-92/5.137.z cells specifically lysed gastric cancer cells expressing HER2 and had higher levels of cytokine production. In vivo, NK-92/5.137.z cells were particularly efficient at eliminating small tumor xenografts, whereas larger solid tumors were not effectively controlled with NK-92/5.137.z cells. Treatment with apatinib increased NK cell infiltration into large tumor xenografts and improved the therapeutic efficacy of NK-92/5.137.z cells. CONCLUSION: NK-92/5.137.z cells could represent a novel treatment option for patients with gastric cancer, either used alone or combined with apatinib.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/imunologia , Piridinas/uso terapêutico , Receptor ErbB-2/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Neoplasias Gástricas/terapia , Animais , Antígeno CD56/metabolismo , Degranulação Celular , Linhagem Celular Tumoral , Terapia Combinada/métodos , Xenoenxertos , Humanos , Células Matadoras Naturais/fisiologia , Células Matadoras Naturais/transplante , Lentivirus , Camundongos , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Carga Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo
3.
Pediatr Blood Cancer ; 66(11): e27964, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31407508

RESUMO

Secondary hemophagocytic syndrome (HPS) has been described after autologous hematopoietic cell transplant (AutoHCT). We report two cases of secondary HPS after novel consolidation therapy for high-risk neuroblastoma as part of an institutional phase 2 trial incorporating immunotherapy into a "standard" AutoHCT regimen. Both patients developed liver dysfunction beyond expected course of hepatic veno-occlusive disease, coagulopathy, hyperferritinemia, and when evaluated, elevated soluble interleukin-2 receptor and hemophagocytosis. These cases highlight the need for clinicians to have a high index of suspicion for immune-related complications in patients receiving immune therapies.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia/efeitos adversos , Células Matadoras Naturais/transplante , Falência Hepática/etiologia , Linfo-Histiocitose Hemofagocítica/etiologia , Neuroblastoma/terapia , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano/administração & dosagem , Bussulfano/efeitos adversos , Pré-Escolar , Ferritinas/sangue , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Lactente , Falência Hepática/terapia , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Neuroblastoma/tratamento farmacológico , Síndrome de Resposta Inflamatória Sistêmica/terapia , Condicionamento Pré-Transplante/efeitos adversos
4.
ACS Appl Mater Interfaces ; 11(37): 33716-33724, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31454227

RESUMO

Immunotherapy has recently garnered significant research interest in the field of clinical cancer management. The potential of tumor immunotherapy has been demonstrated for targeting a variety of tumors, both in vivo and in vitro, yielding some remarkable therapeutic effects. Herein, inspired by the stem cell niche, we developed a scale-up approach to generating porous microspheres with encapsulated natural killer (NK) cells via microfluidic electrospray for in situ tumor immunotherapy. The generated microspheres contained porous microstructures with tunable morphologies because of versatile but precise fluid control in the microfluidic electrospray system. NK-92MI cells encapsulated in porous microspheres were protected from the outer complex environment, allowing for improved proliferation and functionality. As observed, perforin and granzymes were sustainably secreted from the encapsulated NK-92MI cells, which exhibited robust killing effects on tumors both in vitro and in vivo. With continual proliferation, NK-92MI cells budded from the surface of porous microspheres and migrated into the surrounding residual tumor tissues, further destroying tumor cells. More importantly, no side effects owing to the native host immune system were observed by injecting the NK-92MI cell-encapsulated microspheres into tumors in vivo. Therefore, the NK-cell-encapsulated porous microspheres show great potential for tumor immunotherapy, offering a robust and attractive treatment option for cancer patient management.


Assuntos
Células Imobilizadas , Imunidade Celular , Imunoterapia , Células Matadoras Naturais , Microesferas , Neoplasias Experimentais , Animais , Linhagem Celular Tumoral , Células Imobilizadas/imunologia , Células Imobilizadas/patologia , Células Imobilizadas/transplante , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Células Matadoras Naturais/transplante , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia , Porosidade
5.
Int J Mol Sci ; 20(13)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261712

RESUMO

(1) Background: Immune cell therapy recently attracted enormous attention among scientists as a cancer treatment, but, so far, it has been poorly studied and applied in Vietnam. The aim of this study was to assess the safety of autologous immune cell therapy for treating lung, liver, and colon cancers-three prevalent cancers in Vietnam. (2) Method: This was an open-label, single-group clinical trial that included 10 patients with confirmed diagnosis of colon, liver, or lung cancer, conducted between March 2016 and December 2017. (3) Results: After 20-21 days of culture, the average number of cytotoxic T lymphocytes (CTLs) increased 488.5-fold and the average cell viability was 96.3%. The average number of natural killer cells (NKs) increased 542.5-fold, with an average viability of 95%. Most patients exhibited improved quality of life, with the majority of patients presenting a score of 1 to 2 in the Eastern Cooperative Oncology Group (ECOG) performance status (ECOG/PS) scale, a decrease in symptoms on fatigue scales, and an increase in the mean survival time to 18.7 months at the end of the study. (4) Conclusion: This method of immune cell expansion met the requirements for clinical applications in cancer treatment and demonstrated the safety of this therapy for the cancer patients in Vietnam.


Assuntos
Neoplasias do Colo/terapia , Imunoterapia/métodos , Células Matadoras Naturais/transplante , Neoplasias Hepáticas/terapia , Neoplasias Pulmonares/terapia , Linfócitos T Citotóxicos/transplante , Adulto , Idoso , Idoso de 80 Anos ou mais , Transfusão de Sangue Autóloga/métodos , Células Cultivadas , Feminino , Humanos , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T Citotóxicos/imunologia
6.
Pediatr Blood Cancer ; 66(10): e27783, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31304677

RESUMO

Natural killer (NK) cells have potential utility in pediatric cancer immunotherapy for their ability to lyse diverse tumor targets, lack of dependence on mutation-associated tumor antigens, and for their relative safety demonstrated so far in clinical trials. Here, we evaluate the cytotoxic potential of expanded NK cells against a well-characterized panel of pediatric cancer cell lines representing Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, lymphoma, leukemia, and brain tumors. We correlate their sensitivity NK cell lysis with tumor phenotypic, transcriptomic, and genetic determinants, and correlate known immunogenetic determinants with donor NK cell potency. Although ligand expression on cell lines stratified according to hematologic versus nonhematologic cancer types, the sensitivity to NK cell lysis varied widely and did not correlate with cancer type, expression of individual activating or inhibitory ligands, gene-expression clusters of NK cell ligands, disease status (newly diagnosed or relapsed), or MYCN amplification. Rather, sensitivity to NK cell-mediated lysis was associated with a novel 96-gene cluster of predominantly carcinoma-, apoptosis-, and cell death-related pathways, and with functional p53 status. NK cell potency was strongly associated with activating KIR gene content, but not with KIR/KIR-ligand mismatch. This study suggests that adoptive immunotherapy with expanded NK cells has the potential for a wide range of pediatric cancers, identifies potential biomarkers of efficacy and response, and establishes a foundation for using this cell line panel for the preclinical evaluation of immunotherapies.


Assuntos
Citotoxicidade Imunológica/imunologia , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Transcriptoma , Apoptose/imunologia , Carcinoma/imunologia , Carcinoma/patologia , Linhagem Celular Tumoral , Humanos , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/transplante , Neoplasias/patologia
7.
Int J Mol Sci ; 20(14)2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31311121

RESUMO

Relapsed acute myeloid leukemia (AML) is a significant post-transplant complication lacking standard treatment and associated with a poor prognosis. Cellular therapy, which is already widely used as a treatment for several hematological malignancies, could be a potential treatment alternative. Natural killer (NK) cells play an important role in relapse control but can be inhibited by the leukemia cells highly positive for HLA class I. In order to restore NK cell activity after their ex vivo activation, NK cells can be combined with conditioning target cells. In this study, we tested NK cell activity against KG1a (AML cell line) with and without two types of pretreatment-Ara-C treatment that induced NKG2D ligands (increased activating signal) and/or blocking of HLA-KIR (killer-immunoglobulin-like receptors) interaction (decreased inhibitory signal). Both treatments improved NK cell killing activity. Compared with target cell killing of NK cells alone (38%), co-culture with Ara-C treated KG1a target cells increased the killing to 80%. Anti-HLA blocking antibody treatment increased the proportion of dead KG1a cells to 53%. Interestingly, the use of the combination treatment improved the killing potential to led to the death of 85% of KG1a cells. The combination of Ara-C and ex vivo activation of NK cells has the potential to be a feasible approach to treat relapsed AML after hematopoietic stem cell transplantation.


Assuntos
Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/terapia , Linhagem Celular Tumoral , Células Cultivadas , Ensaios Clínicos como Assunto , Citarabina/farmacologia , Humanos , Imunossupressores/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/transplante , Leucemia Mieloide Aguda/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Receptores KIR/imunologia , Transdução de Sinais
8.
Cancer Immunol Immunother ; 68(6): 961-971, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30955067

RESUMO

Hepatocellular carcinoma (HCC) is the third most lethal cancer in the world. Natural killer (NK) cell-mediated immunity is crucial for tumor surveillance and therapy. Characterization of the regulatory mechanisms of NK cell function is important for developing novel immunotherapies against HCC. In this study, we used a chemical-induced mouse HCC model to identify the upregulation of Sirtuin2 (SIRT2) in liver NK cells. In particular, SIRT2 was predominantly expressed in liver CD94+ NK cells. The HCC liver microenvironment induced SIRT2 expression in NK cells. In addition, overexpression of exogenous SIRT2 significantly upregulated the production of cytokines and cytotoxic mediators in activated NK cells. Consistently, SIRT2-overexpressing NK cells showed a stronger tumoricidal effect on hepatoma cells. Moreover, SIRT2 remarkably promoted the phosphorylation of Extracellular-signal-regulated kinase 1/2 (Erk1/2) and p38 Mitogen-activated protein kinases (MAPK) in activated NK cells. SIRT2 knockdown in liver CD94+ NK cells impaired their cytotoxic effect on hepatoma cells. Our study indicates that SIRT2 enhances the tumoricidal activity of liver NK cells in HCC.


Assuntos
Carcinoma Hepatocelular/imunologia , Citotoxicidade Imunológica/imunologia , Células Matadoras Naturais/imunologia , Neoplasias Hepáticas Experimentais/imunologia , Fígado/imunologia , Sirtuína 2/imunologia , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Citocinas/imunologia , Citocinas/metabolismo , Citotoxicidade Imunológica/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/imunologia , Humanos , Imunoterapia Adotiva , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/transplante , Fígado/metabolismo , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/terapia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Interferência de RNA , Sirtuína 2/genética , Sirtuína 2/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Int J Cancer ; 145(7): 1935-1945, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30860598

RESUMO

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells represent a promising effector cell type for adoptive cancer immunotherapy. Both, genetically modified donor-derived NK cells as well as continuously expanding NK-92 cells are currently under clinical development. To enhance their therapeutic utility for the treatment of pre-B-cell acute lymphoblastic leukemia (B-ALL), we engineered NK-92 cells by lentiviral gene transfer to express a FMS-like tyrosine kinase 3 (FLT3)-specific CAR that contains a composite CD28-CD3ζ signaling domain. FLT3 has primarily been described as a therapeutic target for acute myeloid leukemia, but overexpression of FLT3 has also been reported in B-ALL. Exposure of FLT3-positive targets to CAR NK-92 cells resulted in conjugate formation between NK and leukemia cells, NK-cell degranulation and selective cytotoxicity toward established B-ALL cell lines and primary blasts that were resistant to parental NK-92. In a SEM B-ALL xenograft model in NOD-SCID IL2R γnull mice, treatment with CAR NK-92 but not parental NK-92 cells markedly inhibited disease progression, demonstrating high antileukemic activity in vivo. As FLT3 is known to be also expressed on precursor cells, we assessed the feasibility of incorporating an inducible caspase-9 (iCasp9) suicide switch to enhance safety of our approach. Upon addition of the chemical dimerizer AP20187 to NK-92 cells coexpressing the FLT3-specific CAR and iCasp9, rapid iCasp9 activation was observed, precluding further CAR-mediated cytotoxicity. Our data demonstrate that B-ALL can be effectively targeted by FLT3-specific CAR NK cells which may complement CD19-directed immunotherapies, particularly in cases of inherent or acquired resistance to the latter.


Assuntos
Imunoterapia Adotiva/métodos , Células Matadoras Naturais/transplante , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos Quiméricos/metabolismo , Tirosina Quinase 3 Semelhante a fms/imunologia , Animais , Linhagem Celular Tumoral , Engenharia Genética , Células HL-60 , Humanos , Subunidade gama Comum de Receptores de Interleucina/genética , Células Matadoras Naturais/imunologia , Camundongos Endogâmicos NOD , Camundongos SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Strahlenther Onkol ; 195(4): 352-361, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30747241

RESUMO

BACKGROUND: Membrane heat shock protein 70 (mHsp70) is indicative of high-risk tumors and serves as a tumor-specific target for natural killer (NK) cells stimulated with Hsp70 peptide (TKD) and Interleukin(IL)-2. Radiochemotherapy (RCT), mHsp70-targeting NK cells, and programmed death(PD)-1 inhibition were combined to improve the efficacy of tumor-specific immune cells in a non-small cell lung carcinoma (NSCLC) patient. PATIENT: Following simultaneous RCT (64.8 Gy), a patient with inoperable NSCLC (cT4, cN3, cM0, stage IIIb) was treated with 4 cycles of autologous ex vivo TKD/IL-2-activated NK cells and the PD-1 antibody nivolumab as a second-line therapy. Blood samples were taken for immunophenotyping during the course of therapy. RESULTS: Adoptive transfer of ex vivo TKD/IL-2-activated NK cells after RCT combined with PD-1 blockade is well tolerated and results in superior overall survival (OS). No viable tumor cells but a massive immune cell infiltration in fibrotic tissue was detected after therapy. Neither tumor progression nor distant metastases were detectable by CT scanning 33 months after diagnosis. Therapy response was associated with significantly increased CD3-/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell and CD3-/CD56bright to CD3-/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood. CONCLUSION: A combined therapy consisting of RCT, mHsp70-targeting NK cells, and PD-1 antibody inhibition is well tolerated, induces anti-tumor immunity, and results in long-term tumor control in one patient with advanced NSCLC. Further, randomized studies are necessary to confirm the efficacy of this combination therapy.


Assuntos
Transferência Adotiva , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimiorradioterapia/métodos , Células Matadoras Naturais/transplante , Neoplasias Pulmonares/terapia , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Terapia Combinada , Proteínas de Choque Térmico HSP70/sangue , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Planejamento da Radioterapia Assistida por Computador , Tomografia Computadorizada por Raios X
11.
J Neurooncol ; 142(3): 395-407, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30788681

RESUMO

PURPOSE: Medulloblastoma (MB) is the most common malignant brain tumor in children. Recent studies have shown the ability of natural killer (NK) cells to lyse MB cell lines in vitro, but in vivo successes remain elusive and the efficacy and fate of NK cells in vivo remain unknown. METHODS: To address these questions, we injected MB cells into the cerebellum of immunodeficient mice and examined tumor growth at various days after tumor establishment via bioluminescence imaging. NK cells were labeled with a fluorine-19 (19F) MRI probe and subsequently injected either intratumorally or contralaterally to the tumor in the cerebellum and effect on tumor growth was monitored. RESULTS: The 19F probe efficiently labeled the NK cells and exhibited little cytotoxicity. Fluorine-19 MRI confirmed the successful and accurate delivery of the labeled NK cells to the cerebellum of the mice. Administration of 19F-labeled NK cells suppressed MB growth, with the same efficacy as unlabeled cells. Immunohistochemistry confirmed the presence of NK cells within the tumor, which was associated with induction of apoptosis in tumor cells. NK cell migration to the tumor from a distal location as well as activation of apoptosis was also demonstrated by immunohstochemistry. CONCLUSIONS: Our results show that NK cells present a novel opportunity for new strategies in MB treatment. Further, 19F-labeled NK cells can suppress MB growth while enabling 19F MRI to provide imaging feedback that can facilitate study and optimization of therapeutic paradigms.


Assuntos
Neoplasias Cerebelares/prevenção & controle , Monitoramento de Medicamentos/métodos , Radioisótopos de Flúor/uso terapêutico , Células Matadoras Naturais/transplante , Imagem por Ressonância Magnética/métodos , Meduloblastoma/prevenção & controle , Animais , Apoptose , Proliferação de Células , Neoplasias Cerebelares/imunologia , Neoplasias Cerebelares/patologia , Humanos , Meduloblastoma/imunologia , Meduloblastoma/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Bioconjug Chem ; 30(3): 552-560, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30779553

RESUMO

We report the generation of magnetically responsive, cord blood-derived natural killer (NK) cells using iron oxide nanoparticles (IONPs). NK cells are a promising immune cell population for cancer cell therapy as they can target and lyse target tumor cells without prior education. However, NK cells cannot home to disease sites based on antigen recognition, instead relying primarily on external stimuli and chemotactic gradients for transport. Hence, we hypothesized that conjugating IONPs onto the surface of NK cells provides an added feature of magnetic homing to the NK cells, improving their therapeutic function. We describe a robust design for conjugating the IONPs onto the surface of NK cells, which maintains their intrinsic phenotype and function. The conferred magnetic-responsiveness is utilized to improve the cytolytic function of the NK cells for target cells in 2D and 3D models. These findings demonstrate the feasibility of improving NK cell homing and therapeutic efficacy with our NK:IONP "biohybrid".


Assuntos
Sangue Fetal/citologia , Células Matadoras Naturais/citologia , Nanopartículas de Magnetita/química , Linhagem Celular Tumoral , Células Cultivadas , Células Imobilizadas/citologia , Células Imobilizadas/imunologia , Células Imobilizadas/transplante , Humanos , Imunoterapia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/transplante , Nanopartículas de Magnetita/uso terapêutico , Nanomedicina , Neoplasias/imunologia , Neoplasias/terapia
14.
Bone Marrow Transplant ; 54(1): 26-34, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29795426

RESUMO

Despite recent advances in reducing therapy-related mortality after allogeneic stem cell transplantation (alloSCT) relapse remains the major cause of treatment failure and little progress has been achieved in the last decades. At the 3rd International Workshop on Biology, Prevention, and Treatment of Relapse held in Hamburg/Germany in November 2016 international experts presented and discussed recent developments in the field. Here, the potential of cellular therapies including unspecific and specific T cells, genetically modified T cells, CAR-T cells, NK-cells, and second allografting in prevention and treatment of relapse after alloSCT are summarized.


Assuntos
Imunoterapia Adotiva , Células Matadoras Naturais/transplante , Transplante de Células-Tronco , Linfócitos T/transplante , Aloenxertos , Humanos , Recidiva
15.
Cardiovasc Intervent Radiol ; 42(1): 48-59, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30151798

RESUMO

PURPOSE: This study aimed to investigate the safety and short-term efficacy of irreversible electroporation (IRE) combined with allogenic natural killer (NK) cell immunotherapy in the treatment of patients with unresectable primary liver cancer. MATERIALS AND METHODS: Between October 2015 and December 2016, 40 patients were enrolled and randomly allocated to either the IRE group (n = 22) or the IRE-NK group (n = 18). All adverse events experienced by the patients were recorded; the changes in tumor biomarkers [AFP, CA 19-9, circulating tumor cells (CTCs)], lymphocyte number and function, quality of life, clinical response, progression-free survival (PFS) and overall survival (OS) were assessed. RESULTS: Patients who received combination therapy exhibited significantly longer median PFS and OS than who just received IRE (PFS 15.1 vs. 10.6 months, P < 0.05, OS 17.9 vs. 23.2 months, P < 0.05). The combination therapy of IRE and NK cell immunotherapy significantly reduced CTCs and increased immune function and Karnofsky performance status. CONCLUSION: Our data suggest a novel, promising combination therapy using IRE and allogenic NK cell immunotherapy. Larger clinical trials are required to confirm these conclusions.


Assuntos
Eletroporação , Imunoterapia Adotiva , Células Matadoras Naturais/transplante , Neoplasias Hepáticas/terapia , Adulto , Idoso , Biomarcadores Tumorais/sangue , Terapia Combinada , Feminino , Humanos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Células Neoplásicas Circulantes , Intervalo Livre de Progressão , Estudos Prospectivos , Resultado do Tratamento
16.
Clin Cancer Res ; 25(1): 325-333, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30232225

RESUMO

PURPOSE: Immunotherapy of neuroblastoma that remains after myeloablative chemotherapy with anti-GD2 antibody dinutuximab has increased the two-year event-free and overall survival of high-risk neuroblastoma patients; however, 40% of patients develop recurrent disease during or after this treatment. To determine the potential of such antibody-based immunotherapy earlier in treatment, a mouse model was developed in which surgical resection of the primary tumor was followed by therapy of residual disease with dinutuximab combined with ex vivo-activated human natural killer (aNK) cells. EXPERIMENTAL DESIGN: The effect of combining dinutuximab with human aNK cells was determined in vitro with cellular cytotoxicity and Matrigel invasion assays. The in vivo efficacy of dinutuximab and aNK cells against neuroblastoma was assessed following resection of primary tumors formed by two cell lines or a patient-derived xenograft (PDX) in immunodeficient NOD-scid gamma mice. RESULTS: In vitro, the combination of aNK cells and dinutuximab caused cytotoxicity and decreased invasiveness of three human neuroblastoma cell lines. Treatment of mice with dinutuximab combined with aNK cells after surgical resection of primary intrarenal tumors formed by two cell lines or a PDX decreased tumor cells in liver and bone marrow as evaluated by histopathology and bioluminescence imaging. Survival of mice after resection of these tumors was most significantly increased by treatment with dinutuximab combined with aNK cells compared with that of untreated mice. CONCLUSIONS: The combination of dinutuximab and adoptively transferred human aNK cells following surgical resection of primary neuroblastomas significantly improves survival of immunodeficient mice.


Assuntos
Anticorpos Anti-Idiotípicos/farmacologia , Anticorpos Monoclonais/farmacologia , N-Acetilgalactosaminiltransferases/genética , Neuroblastoma/terapia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Terapia Combinada , Citotoxicidade Imunológica/efeitos dos fármacos , Modelos Animais de Doenças , Xenoenxertos , Humanos , Imunoterapia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/transplante , Camundongos , N-Acetilgalactosaminiltransferases/antagonistas & inibidores , Neuroblastoma/imunologia , Neuroblastoma/cirurgia
17.
Front Immunol ; 9: 2552, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30455699

RESUMO

Elimination of the latent HIV reservoir remains the biggest hurdle to achieve HIV cure. In order to specifically eliminate HIV infected cells they must be distinguishable from uninfected cells. CD2 was recently identified as a potential marker enriched in the HIV-1 reservoir on CD4+ T cells, the largest, longest-lived and best-characterized constituent of the HIV reservoir. We previously proposed to repurpose FDA-approved alefacept, a humanized α-CD2 fusion protein, to reduce the HIV reservoir in CD2hi CD4+ memory T cells. Here, we show the first evidence that alefacept can specifically target and reduce CD2hi HIV infected cells in vitro. We explore a variety of natural killer (NK) cells as mediators of antibody-dependent cell-mediated cytotoxicity (ADCC) including primary NK cells, expanded NK cells as well as the CD16 transduced NK-92 cell line which is currently under study in clinical trials as a treatment for cancer. We demonstrate that CD16.NK-92 has a natural preference to kill CD2hi CD45RA- memory T cells, specifically CD45RA- CD27+ central memory/transitional memory (TCM/TM) subset in both healthy and HIV+ patient samples as well as to reduce HIV DNA from HIV+ samples from donors well controlled on antiretroviral therapy. Lastly, alefacept can combine with CD16.NK-92 to decrease HIV DNA in some patient samples and thus may yield value as part of a strategy toward sustained HIV remission.


Assuntos
Alefacept/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/transplante , Latência Viral/efeitos dos fármacos , Transferência Adotiva , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Biomarcadores/metabolismo , Antígenos CD2/imunologia , Linfócitos T CD4-Positivos/virologia , Linhagem Celular , DNA Viral/genética , Quimioterapia Combinada , Proteínas Ligadas por GPI/metabolismo , HIV-1/imunologia , Humanos , Memória Imunológica/imunologia , Células Jurkat , Células Matadoras Naturais/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Receptores de IgG/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
18.
J Immunol Res ; 2018: 4263520, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30410941

RESUMO

Adoptive chimeric antigen receptor-modified T or NK cells (CAR-T or CAR-NK) offer new options for cancer treatment. CAR-T therapy has achieved encouraging breakthroughs in the treatment of hematological malignancies. However, their therapeutic efficacy against solid tumors is limited. New regimens, including combinations with chemical drugs, need to be studied to enhance the therapeutic efficacy of CAR-T or NK cells for solid tumors. An epithelial cell adhesion molecule- (EpCAM-) specific second-generation CAR was constructed and transduced into NK-92 cells by lentiviral vectors. Immune effects, including cytokine release and cytotoxicity of the CAR-NK-92 cells against EpCAM-positive colon cancer cells, were evaluated in vitro. Synergistic effects of regorafenib and CAR-NK-92 cells were analyzed in a mouse model with human colorectal cancer xenografts. The CAR-NK-92 cells can specifically recognize EpCAM-positive colorectal cancer cells and release cytokines, including IFN-γ, perforin, and granzyme B, and show specific cytotoxicity in vitro. The growth suppression efficacy of combination therapy with regorafenib and CAR-NK-92 cells on established EpCAM-positive tumor xenografts was more significant than that of monotherapy with CAR-NK-92 cells or regorafenib. Our results provided a novel strategy to treat colorectal cancer and enhance the therapeutic efficacy of CAR-modified immune effector cells for solid tumors.


Assuntos
Antineoplásicos/uso terapêutico , Vacinas Anticâncer/imunologia , Neoplasias Colorretais/terapia , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/fisiologia , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/imunologia , Terapia Combinada , Citotoxicidade Imunológica , Modelos Animais de Doenças , Molécula de Adesão da Célula Epitelial/imunologia , Feminino , Humanos , Interferon gama/metabolismo , Células Matadoras Naturais/transplante , Camundongos , Camundongos SCID , Receptores de Antígenos Quiméricos/genética , Carga Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto
19.
J Immunol Res ; 2018: 4054815, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30306093

RESUMO

Natural killer (NK) cells are powerful immune effectors whose antitumor activity is regulated through a sophisticated network of activating and inhibitory receptors. As effectors of cancer immunotherapy, NK cells are attractive as they do not attack healthy self-tissues nor do they induce T cell-driven inflammatory cytokine storm, enabling their use as allogeneic adoptive cellular therapies. Clinical responses to adoptive NK-based immunotherapy have been thwarted, however, by the profound immunosuppression induced by the tumor microenvironment, particularly severe in the context of solid tumors. In addition, the short postinfusion persistence of NK cells in vivo has limited their clinical efficacy. Enhancing the antitumor immunity of NK cells through genetic engineering has been fueled by the promise that impaired cytotoxic functionality can be restored or augmented with the use of synthetic genetic approaches. Alongside expressing chimeric antigen receptors to overcome immune escape by cancer cells, enhance their recognition, and mediate their killing, NK cells have been genetically modified to enhance their persistence in vivo by the expression of cytokines such as IL-15, avoid functional and metabolic tumor microenvironment suppression, or improve their homing ability, enabling enhanced targeting of solid tumors. However, NK cells are notoriously adverse to endogenous gene uptake, resulting in low gene uptake and transgene expression with many vector systems. Though viral vectors have achieved the highest gene transfer efficiencies with NK cells, nonviral vectors and gene transfer approaches-electroporation, lipofection, nanoparticles, and trogocytosis-are emerging. And while the use of NK cell lines has achieved improved gene transfer efficiencies particularly with viral vectors, challenges with primary NK cells remain. Here, we discuss the genetic engineering of NK cells as they relate to NK immunobiology within the context of cancer immunotherapy, highlighting the most recent breakthroughs in viral vectors and nonviral approaches aimed at genetic reprogramming of NK cells for improved adoptive immunotherapy of cancer, and, finally, address their clinical status.


Assuntos
Vacinas Anticâncer/imunologia , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/fisiologia , Neoplasias/terapia , Animais , Técnicas de Reprogramação Celular , Engenharia Genética , Vetores Genéticos/genética , Humanos , Células Matadoras Naturais/transplante , Neoplasias/imunologia , Vírus/genética
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