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1.
N Engl J Med ; 382(14): 1331-1342, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32242358

RESUMO

BACKGROUND: Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton's tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma. METHODS: In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×106 CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months. RESULTS: A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval [CI], 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred. CONCLUSIONS: KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313.).


Assuntos
Antígenos CD19/uso terapêutico , Imunoterapia Adotiva , Linfoma de Célula do Manto/terapia , Receptores de Antígenos Quiméricos/antagonistas & inibidores , Adulto , Idoso , Antineoplásicos/uso terapêutico , Terapia Combinada , Humanos , Imunoterapia Adotiva/efeitos adversos , Infusões Intravenosas , Leucaférese , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/mortalidade , Pessoa de Meia-Idade , Recidiva , Análise de Sobrevida , Linfócitos T/transplante , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico
2.
Nat Commun ; 11(1): 798, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034142

RESUMO

Multiple myeloma (MM) is a plasma cell malignancy and most patients eventually succumb to the disease. Chimeric antigen receptor (CAR) T cells targeting B-Cell Maturation Antigen (BCMA) on MM cells have shown high-response rates, but limited durability. CD229/LY9 is a cell surface receptor present on B and T lymphocytes that is universally and strongly expressed on MM plasma cells. Here, we develop CD229 CAR T cells that are highly active in vitro and in vivo against MM plasma cells, memory B cells, and MM-propagating cells. We do not observe fratricide during CD229 CAR T cell production, as CD229 is downregulated in T cells during activation. In addition, while CD229 CAR T cells target normal CD229high T cells, they spare functional CD229neg/low T cells. These findings indicate that CD229 CAR T cells may be an effective treatment for patients with MM.


Assuntos
Imunoterapia Adotiva/métodos , Mieloma Múltiplo/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Animais , Anticorpos/imunologia , Linfócitos B/metabolismo , Humanos , Células K562/imunologia , Masculino , Camundongos Endogâmicos NOD , Mieloma Múltiplo/patologia , Receptores de Antígenos de Linfócitos T/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Linfócitos T/transplante , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Science ; 367(6481)2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32029687

RESUMO

CRISPR-Cas9 gene editing provides a powerful tool to enhance the natural ability of human T cells to fight cancer. We report a first-in-human phase 1 clinical trial to test the safety and feasibility of multiplex CRISPR-Cas9 editing to engineer T cells in three patients with refractory cancer. Two genes encoding the endogenous T cell receptor (TCR) chains, TCRα (TRAC) and TCRß (TRBC), were deleted in T cells to reduce TCR mispairing and to enhance the expression of a synthetic, cancer-specific TCR transgene (NY-ESO-1). Removal of a third gene encoding programmed cell death protein 1 (PD-1; PDCD1), was performed to improve antitumor immunity. Adoptive transfer of engineered T cells into patients resulted in durable engraftment with edits at all three genomic loci. Although chromosomal translocations were detected, the frequency decreased over time. Modified T cells persisted for up to 9 months, suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of CRISPR gene editing for cancer immunotherapy.


Assuntos
Transferência Adotiva , Sistemas CRISPR-Cas , Edição de Genes , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/imunologia , Linfócitos T/transplante , Idoso , Proteína 9 Associada à CRISPR , Engenharia Celular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Transgenes
5.
Nat Rev Drug Discov ; 19(3): 185-199, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900462

RESUMO

Autologous chimeric antigen receptor (CAR) T cells have changed the therapeutic landscape in haematological malignancies. Nevertheless, the use of allogeneic CAR T cells from donors has many potential advantages over autologous approaches, such as the immediate availability of cryopreserved batches for patient treatment, possible standardization of the CAR-T cell product, time for multiple cell modifications, redosing or combination of CAR T cells directed against different targets, and decreased cost using an industrialized process. However, allogeneic CAR T cells may cause life-threatening graft-versus-host disease and may be rapidly eliminated by the host immune system. The development of next-generation allogeneic CAR T cells to address these issues is an active area of research. In this Review, we analyse the different sources of T cells for optimal allogeneic CAR-T cell therapy and describe the different technological approaches, mainly based on gene editing, to produce allogeneic CAR T cells with limited potential for graft-versus-host disease. These improved allogeneic CAR-T cell products will pave the way for further breakthroughs in the treatment of cancer.


Assuntos
Doença Enxerto-Hospedeiro/terapia , Imunoterapia/métodos , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Linfócitos T/transplante , Doença Enxerto-Hospedeiro/imunologia , Humanos , Neoplasias/imunologia , Transplante Homólogo
6.
Science ; 367(6476): 446-453, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31896660

RESUMO

Chimeric antigen receptor (CAR)-T cells have shown efficacy in patients with B cell malignancies. Yet, their application for solid tumors has challenges that include limited cancer-specific targets and nonpersistence of adoptively transferred CAR-T cells. Here, we introduce the developmentally regulated tight junction protein claudin 6 (CLDN6) as a CAR target in solid tumors and a strategy to overcome inefficient CAR-T cell stimulation in vivo. We demonstrate that a nanoparticulate RNA vaccine, designed for body-wide delivery of the CAR antigen into lymphoid compartments, stimulates adoptively transferred CAR-T cells. Presentation of the natively folded target on resident antigen-presenting cells promotes cognate and selective expansion of CAR-T cells. Improved engraftment of CAR-T cells and regression of large tumors in difficult-to-treat mouse models was achieved at subtherapeutic CAR-T cell doses.


Assuntos
Vacinas Anticâncer/uso terapêutico , Claudinas/antagonistas & inibidores , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Animais , Claudinas/imunologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , RNA/uso terapêutico , Linfócitos T/imunologia , Linfócitos T/transplante , Vacinas Sintéticas/uso terapêutico
7.
Mol Carcinog ; 59(2): 237-245, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31898340

RESUMO

In humans, bone marrow (BM) failure syndromes, both constitutional and acquired, predispose to myeloid malignancies. We have modeled acquired immune aplastic anemia, the paradigmatic disease of these syndromes, in the mouse by infusing lymph node cells from specific pathogen-free (SPF) CD45.1 congenic C57BL/6 (B6) donors into hybrid CByB6F1 recipients housed either in conventional (CVB) or SPF facilities. The severity of BM damage was reduced in CVB recipients; they also had reduced levels of CD44+ CD62L- effector memory T cells, reduced numbers of donor-type CD44+ T cells, and reduced expansion of donor-type CD8 T cells carrying T-cell receptor ß-variable regions 07, 11, and 17. Analyses of fecal samples through 16S ribosomal RNA amplicon sequencing revealed greater gut microbial alpha diversity in CVB mice relative to that of SPF mice. Thus, the presence of a broader spectrum of gut microorganisms in CVB-housed CByB6F1 could have primed recipient animal's immune system leading to suppression of allogeneic donor T-cell activation and expansion and attenuation of host BM destruction. These results suggest the potential benefit of diverse gut microbiota in patients receiving BM transplants.


Assuntos
Anemia Aplástica/terapia , Transplante de Medula Óssea/métodos , Medula Óssea/imunologia , Microbioma Gastrointestinal/imunologia , Linfócitos T/imunologia , Anemia Aplástica/imunologia , Anemia Aplástica/patologia , Animais , Medula Óssea/patologia , Fezes/microbiologia , Receptores de Hialuronatos/imunologia , Receptores de Hialuronatos/metabolismo , Memória Imunológica/imunologia , Ativação Linfocitária/imunologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Organismos Livres de Patógenos Específicos , Linfócitos T/metabolismo , Linfócitos T/transplante , Imunologia de Transplantes , Transplante Homólogo
8.
Pediatr Blood Cancer ; 67(3): e28126, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31850668

RESUMO

Children with ataxia telangiectasia (AT), a primary immunodeficiency caused by mutations in ATM, which is critical for repairing DNA defects, are at risk for the development of hematologic malignancy, frequently driven by infection with Epstein-Barr virus (EBV). Conventional chemotherapy is poorly tolerated by patients with AT, with excessive toxicity even when doses are reduced. Here, we report on two patients with AT and EBV-positive neoplasms who were treated with EBV-targeted viral-specific T cells (VST). One patient had a prolonged complete response to VSTs while the other had a partial response. Therapy was well tolerated without infusion toxicity or graft-versus-host disease.


Assuntos
Ataxia Telangiectasia/terapia , Reparo do DNA/genética , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/genética , Doença de Hodgkin/terapia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Linfócitos T/transplante , Ataxia Telangiectasia/etiologia , Ataxia Telangiectasia/patologia , Proteínas Mutadas de Ataxia Telangiectasia/genética , Criança , Dano ao DNA , Infecções por Vírus Epstein-Barr/virologia , Feminino , Doença de Hodgkin/etiologia , Doença de Hodgkin/patologia , Humanos , Imunoterapia/métodos , Lactente , Masculino , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Prognóstico , Linfócitos T/imunologia , Ativação Viral
9.
Cancer Metastasis Rev ; 38(4): 611-624, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31811551

RESUMO

The capacity of single-agent therapy with immune checkpoint inhibitors to control solid cancers by unleashing preexisting local antitumor T cell responses has renewed interest in the broader use of T cells as anticancer therapeutics. At the same time, durable responses of refractory B-lineage malignancies to chimeric-receptor engineered T cells illustrate that T cells can be effectively redirected to cancers that lack preexisting tumor antigen-specific T cells, as most typical childhood cancers. This review summarizes strategies by which T cells can be modified to recognize defined antigens, with a focus on chimeric-receptor engineering. We provide an overview of candidate target antigens currently investigated in advanced preclinical and early clinical trials in pediatric malignancies and discuss the prerequisites for an adequate in vivo function of engineered T cells in the microenvironment of solid tumors and intrinsic and extrinsic limitations of current redirected T cell therapies. We further address innovative solutions to recruit therapeutic T cells to tumors, overcome the unreliable and heterogenous expression of most known tumor-associated antigens, and prevent functional inactivation of T cells in the hostile microenvironment of solid childhood tumors.


Assuntos
Imunoterapia Adotiva/métodos , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T/imunologia , Linfócitos T/transplante , Animais , Criança , Humanos , Receptores de Antígenos Quiméricos/imunologia
10.
Cancer Immunol Immunother ; 68(11): 1881-1889, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31595324

RESUMO

Adoptive cell transfer (ACT) using T cell receptor (TCR) gene-modified T cells is an exciting and rapidly evolving field. Numerous preclinical and clinical studies have demonstrated various levels of feasibility, safety, and efficacy using TCR-engineered T cells to treat cancer and viral infections. Although evidence suggests their use can be effective, to what extent and how to improve these therapeutics are still matters of investigation. As TCR affinity has been generally accepted as the central role in defining T cell specificity and sensitivity, selection for and generation of high affinity TCRs has remained a fundamental approach to design more potent T cells. However, traditional methods for affinity-enhancement by random mutagenesis can induce undesirable cross-reactivity causing on- and off-target adverse events, generate exhausted effectors by overstimulation, and ignore other kinetic and cellular parameters that have been shown to impact antigen specificity. In this Focussed Research Review, we comment on the preclinical and clinical potential of TCR gene-modified T cells, summarize our contributions challenging the role TCR affinity plays in antigen recognition, and explore how structure-guided design can be used to manipulate antigen specificity and TCR cross-reactivity to improve the safety and efficacy of TCR gene-modified T cells used in ACT.


Assuntos
Citotoxicidade Imunológica/imunologia , Genes Codificadores dos Receptores de Linfócitos T/imunologia , Imunoterapia , Neoplasias/terapia , Linfócitos T/imunologia , Linfócitos T/transplante , Animais , Especificidade de Anticorpos , Reações Cruzadas , Genes Codificadores dos Receptores de Linfócitos T/genética , Humanos , Neoplasias/imunologia , Neoplasias/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T , Linfócitos T/metabolismo
11.
J Steroid Biochem Mol Biol ; 195: 105485, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31561002

RESUMO

Glucocorticoids (GCs) play an important role in controlling acute graft-versus-host disease (aGvHD), a frequent complication of allogeneic hematopoietic stem cell transplantation. The anti-inflammatory activity of GCs is mainly ascribed to the modulation of T cells and macrophages, for which reason a genetically induced GC resistance of either of these cell types causes aggravated aGvHD. Since only a few genes are currently known that are differentially regulated under these conditions, we analyzed the expression of 54 candidate genes in the inflamed small intestine of mice suffering from aGvHD when either allogeneic T cells or host myeloid cells were GC resistant using a microfluidic dynamic array platform for high-throughput quantitative PCR. The majority of genes categorized as cytokines (e.g. Il2, Il6), chemokines (e.g. Ccl2, Cxcl1), cell surface receptors (e.g. Fasl, Ctla4) and intracellular molecules (e.g. Dusp1, Arg1) were upregulated in mice transplanted with GC resistant allogeneic T cells. Moreover, the expression of several genes linked to energy metabolism (e.g. Glut1) was altered. Surprisingly, mice harboring GC resistant myeloid cells showed almost no changes in gene expression despite their fatal disease course after aGvHD induction. To identify additional genes in the inflamed small intestine that were affected by a GC resistance of allogeneic T cells, we performed an RNAseq analysis, which uncovered more than 500 differentially expressed transcripts (e.g. Cxcr6, Glut3, Otc, Aoc1, Il1r1, Sphk1) that were enriched for biological processes associated with inflammation and tissue disassembly. The changes in gene expression could be confirmed during full-blown disease but hardly any of them in the preclinical phase using high-throughput quantitative PCR. Further analysis of some of these genes revealed a highly selective expression pattern in T cells, intestinal epithelial cells and macrophages, which correlated with their regulation during disease progression. Collectively, we identified an altered gene expression profile caused by GC resistance of transplanted allogeneic T cells, which could help to define new targets for aGvHD therapy.


Assuntos
Resistência a Medicamentos/genética , Glucocorticoides , Doença Enxerto-Hospedeiro/genética , Intestino Delgado/metabolismo , Linfócitos T/transplante , Animais , Doença Enxerto-Hospedeiro/patologia , Intestino Delgado/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Transcriptoma
12.
BioDrugs ; 33(5): 515-537, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31363930

RESUMO

Chimeric antigen receptor-T cells (CAR-Ts) are an exciting new cancer treatment modality exemplified by the recent regulatory approval of two CD19-targeted CAR-T therapies for certain B cell malignancies. However, this success in the hematological setting has yet to translate to a significant level of objective clinical responses in the solid tumor setting. The reason for this lack of translation undoubtedly lies in the substantial challenges raised by solid tumors to all therapies, including CAR-T, that differ from B cell malignancies. For instance, intravenously infused CAR-Ts are likely to make rapid contact with cancerous B cells since both tend to reside in the same vascular compartments within the body. By contrast, solid cancers tend to form discrete tumor masses with an immune-suppressive tumor microenvironment composed of tumor cells and non-tumor stromal cells served by abnormal vasculature that restricts lymphocyte infiltration and suppresses immune function, expansion, and persistence. Moreover, the paucity of uniquely and homogeneously expressed tumor antigens and inherent plasticity of cancer cells provide major challenges to the specificity, potency, and overall effectiveness of CAR-T therapies. This review focuses on the major preclinical and clinical strategies currently being pursued to tackle these challenges in order to drive the success of CAR-T therapy against solid tumors.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Neoplasias/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Microambiente Tumoral/imunologia , Animais , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Ensaios Clínicos como Assunto , Humanos , Neoplasias/imunologia , Linfócitos T/imunologia , Linfócitos T/transplante
13.
Dermatol Clin ; 37(4): 569-582, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31466596

RESUMO

Graft-versus-host disease (GVHD) is an adverse immunologic phenomenon following allogenic hematopoietic stem cell transplant. Cutaneous manifestations are the earliest and most common presentation of the disease. This article describes the pathophysiology, clinical presentation, diagnosis, and treatment options available for acute and chronic GVHD. Acute and chronic GVHD result from an initial insult triggering an exaggerated inflammatory cascade. Clinical presentation for cutaneous acute GVHD is limited to maculopapular rash and oral mucosal lesions, whereas chronic GVHD can also include nail, scalp, and genitalia changes. Diagnosis is often made clinically and supported by biopsy, laboratory and radiology findings.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Dermatopatias/imunologia , Doença Aguda , Corticosteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Doença Crônica , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunoterapia Adotiva/métodos , Dermatopatias/etiologia , Dermatopatias/patologia , Dermatopatias/terapia , Linfócitos T/transplante , Condicionamento Pré-Transplante , Transplante Homólogo
14.
Blood ; 134(11): 860-866, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31320380

RESUMO

Chimeric antigen receptor (CAR) T cells targeting CD19 have emerged as a leading engineered T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma. The phase 1/2 clinical trials that led to US Food and Drug Administration approval excluded patients with central nervous system (CNS) involvement, due to strict eligibility criteria. Here, we report on our institutional experience with 8 secondary CNS lymphoma patients treated with commercial tisagenlecleucel. No patient experienced greater than grade 1 neurotoxicity, and no patient required tocilizumab or steroids for CAR T-cell-mediated toxicities. Biomarker analysis suggested CAR T-cell expansion, despite the absence of systemic disease, and early response assessments demonstrated activity of IV infused CAR T cells within the CNS space.


Assuntos
Neoplasias do Sistema Nervoso Central/secundário , Neoplasias do Sistema Nervoso Central/terapia , Imunoterapia Adotiva/métodos , Linfoma/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Adolescente , Adulto , Idoso , Neoplasias do Sistema Nervoso Central/imunologia , Feminino , Humanos , Linfoma/imunologia , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Linfócitos T/imunologia , Linfócitos T/transplante , Resultado do Tratamento , Adulto Jovem
16.
BioDrugs ; 33(5): 485-501, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31321623

RESUMO

New immuno-oncology therapies are improving cancer treatments beyond the former standard of care, as evidenced by the recent and continuing clinical approvals for immunotherapies in a broad range of indications. However, a majority of patients (particularly those with immunologically cold tumors) still do not benefit, highlighting the need for rational combination approaches. Oncolytic viruses (OV) both directly kill tumor cells and inflame the tumor microenvironment. While OV spread can be limited by the generation of antiviral immune responses, the initial local tumor cell killing can reverse the immunosuppressive tumor microenvironment, resulting in more effective release of tumor-associated antigens (TAAs), cross-presentation, and antitumoral effector T cell recruitment. Moreover, many OVs can be engineered to express immunomodulatory genes. Rational combination approaches to cancer immunotherapy include the use of OVs in combination with immune checkpoint inhibitors (ICIs) or adoptive T cell therapy (ACT) to promote sustained antitumoral immune responses. OV combinations have additive or synergistic efficacy in preclinical tumor models with ICIs or ACT. Several preclinical studies have confirmed systemic reactivation and proliferation of adoptively transferred antitumoral T cells in conjunction with oncolytic OVs (expressing cytokines or TAAs) resulting from the specific tumor cell killing and immunostimulation of the tumor microenvironment which leads to increased tumor trafficking, activity, and survival. Recent clinical trials combining OVs with ICIs have shown additive effects in melanoma. Additional clinical data in an expanded range of patient indications are eagerly awaited. The relative timings of OV and ICI combination remains under-studied and is an area for continued exploration. Studies systematically exploring the effects of systemic ICIs prior to, concomitantly with, or following OV therapy will aid in the future design of clinical trials to enhance efficacy and increase patient response rates.


Assuntos
Neoplasias/imunologia , Neoplasias/terapia , Terapia Viral Oncolítica/métodos , Transferência Adotiva , Animais , Ensaios Clínicos como Assunto , Humanos , Imunoterapia/métodos , Vírus Oncolíticos , Linfócitos T/transplante , Microambiente Tumoral/imunologia
18.
Nat Biotechnol ; 37(12): 1425-1434, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31160723

RESUMO

Autologous T cells that have been genetically modified to express a chimeric antigen receptor (CAR) targeting the B cell antigen CD19 have yielded remarkable clinical responses in patients with B cell malignancies, and are now on the market as anticancer 'drugs'. Riding on this success, the field of immune cell engineering is rapidly growing, with creative solutions to major outstanding challenges, such as limitations in target antigen selection, the hostility of the tumor microenvironment and the logistical challenges of generating autologous therapies. Innovations in antigen receptor design, coupled with advances in gene transfer and gene-editing technologies, have enabled the engineering of T cells to have sophisticated sensing circuits, to have synthetic functionalities, and to be used as off-the-shelf, universal cellular products. As these technologies are applied to other immune cells, such as natural killer cells, hematopoietic cells or induced pluripotent stem cells, the potential to transform the treatment of many cancers, as well as other diseases, is palpably exciting. We discuss the pipeline of several influential innovations in the preclinical setting, the early translational results from clinical trials of these next-generation approaches, and the outlook for gene-modified or gene-edited cell therapies.


Assuntos
Engenharia Celular , Edição de Genes , Imunoterapia Adotiva , Antígenos CD19/imunologia , Antígenos CD19/metabolismo , Humanos , Leucemia de Células B/terapia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/transplante
19.
Nat Commun ; 10(1): 2681, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31213606

RESUMO

Although chimeric antigen receptor (CAR) T cell therapies have demonstrated considerable success in treating hematologic malignancies, they have simultaneously been plagued by a cytokine release syndrome (CRS) that can harm or even kill the cancer patient. We describe a CAR T cell strategy in which CAR T cell activation and cancer cell killing can be sensitively regulated by adjusting the dose of a low molecular weight adapter that must bridge between the CAR T cell and cancer cell to initiate tumor eradication. By controlling the concentration and dosing schedule of adapter administration, we document two methods that can rapidly terminate (<3 h) a pre-existing CRS-like toxicity and two unrelated methods that can pre-emptively prevent a CRS-like toxicity that would have otherwise occurred. Because all four methods concurrently enhance CAR T cell potency, we conclude that proper use of bispecific adapters could potentially avoid a life-threatening CRS while enhancing CAR T cell tumoricidal activity.


Assuntos
Doenças do Sistema Imunitário/prevenção & controle , Imunoterapia Adotiva/efeitos adversos , Neoplasias/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Animais , Engenharia Celular/métodos , Linhagem Celular Tumoral , Citocinas/imunologia , Fluoresceína/metabolismo , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/metabolismo , Humanos , Doenças do Sistema Imunitário/etiologia , Imunoterapia Adotiva/métodos , Ativação Linfocitária/imunologia , Camundongos , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Anticorpos de Cadeia Única/imunologia , Anticorpos de Cadeia Única/metabolismo , Síndrome , Linfócitos T/metabolismo , Linfócitos T/transplante , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Cancer Immunol Immunother ; 68(8): 1235-1243, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31214732

RESUMO

Off-target toxicity due to the expression of target antigens in normal tissue or TCR cross-reactivity represents a major risk when using T cell receptor (TCR)-engineered T cells for treatment of solid tumours. Due to the inherent cross-reactivity of TCRs it is difficult to accurately predict their target recognition pre-clinically. It has become evident that direct testing in a human being represents the best evaluation of the risks. There is, therefore, a clear unmet need for assessing the safety of a therapeutic TCR in a more controllable manner than by the injection of permanently modified cellular products. Using transiently modified T cells combined with dose escalation has already been shown feasible for chimeric antigen receptor (CAR)-engineered T cells, but nothing is yet reported for TCR. We performed a preclinical evaluation of a therapeutic TCR transiently expressed in T cells by mRNA electroporation. We analyzed if the construct was active in vitro, how long it was detectable for and if this expression format was adapted to in vivo efficacy assessment. Our data demonstrate the potential of mRNA engineered T cells, although less powerful than permanent redirection, to induce a significant response. Thus, these findings support the development of mRNA based TCR-therapy strategies as a feasible and efficacious method for evaluating TCR safety and efficacy in first-in-man testing.


Assuntos
Vacinas Anticâncer/imunologia , Neoplasias Colorretais/terapia , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Animais , Neoplasias Colorretais/imunologia , Reações Cruzadas , Citotoxicidade Imunológica , Eletroporação , Células HCT116 , Humanos , Camundongos , Camundongos SCID , Neoplasias Experimentais , RNA Mensageiro/genética , Receptores de Antígenos Quiméricos/genética , Especificidade do Receptor de Antígeno de Linfócitos T , Linfócitos T/transplante , Ensaios Antitumorais Modelo de Xenoenxerto
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