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1.
BMJ Open ; 12(6): e060431, 2022 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-35710239

RESUMO

INTRODUCTION: The prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) is dismal and conventional chemotherapy treatment delivers limited survival improvement. Immunotherapy may complement our current treatment strategies. We previously demonstrated that the combination of an allogeneic tumour-lysate dendritic cell (DC) vaccine with an anti-CD40 agonistic antibody resulted in robust antitumour responses with survival benefit in a murine PDAC model. In the Rotterdam PancrEAtic Cancer Vaccination-2 trial, we aim to translate our findings into patients. This study will determine the safety of DC/anti-CD40 agonistic antibody combination treatment, and treatment-induced tumour-specific immunological responses. METHODS AND ANALYSIS: In this open-label, single-centre (Erasmus Univsersity Medical Center, Rotterdam, Netherlands), single-arm, phase I dose finding study, adult patients with metastatic pancreatic cancer with progressive disease after FOLFIRINOX chemotherapy will receive monocyte-derived DCs loaded with an allogeneic tumour lysate in conjunction with a CD40 agonistic antibody. This combination-immunotherapy regimen will be administered three times every 2 weeks, and booster treatments will be given after 3 and 6 months following the third injection. A minimum of 12 and a maximum of 18 patients will be included. The primary endpoint is safety and tolerability of the combination immunotherapy. To determine the maximum tolerated dose, DCs will be given at a fixed dosage and anti-CD40 agonist in a traditional 3+3 dose-escalation design. Secondary endpoints include radiographic response according to the RECIST (V.1.1) and iRECIST criteria, and the detection of antitumour specific immune responses. ETHICS AND DISSEMINATION: The Central Committee on Research Involving Human Subjects (CCMO; NL76592.000.21) and the Medical Ethics Committee (METC; MEC-2021-0566) of the Erasmus M.C. University Medical Center Rotterdam approved the conduct of the trial. Written informed consent will be required for all participants. The results of the trial will be submitted for publication in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NL9723.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Vacinas Anticâncer , Neoplasias Pancreáticas , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Vacinas Anticâncer/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Células Dendríticas , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas
2.
J Clin Invest ; 131(8)2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33630757

RESUMO

In humans receiving intestinal transplantation (ITx), long-term multilineage blood chimerism often develops. Donor T cell macrochimerism (≥4%) frequently occurs without graft-versus-host disease (GVHD) and is associated with reduced rejection. Here we demonstrate that patients with macrochimerism had high graft-versus-host (GvH) to host-versus-graft (HvG) T cell clonal ratios in their allografts. These GvH clones entered the circulation, where their peak levels were associated with declines in HvG clones early after transplant, suggesting that GvH reactions may contribute to chimerism and control HvG responses without causing GVHD. Consistently, donor-derived T cells, including GvH clones, and CD34+ hematopoietic stem and progenitor cells (HSPCs) were simultaneously detected in the recipients' BM more than 100 days after transplant. Individual GvH clones appeared in ileal mucosa or PBMCs before detection in recipient BM, consistent with an intestinal mucosal origin, where donor GvH-reactive T cells expanded early upon entry of recipient APCs into the graft. These results, combined with cytotoxic single-cell transcriptional profiles of donor T cells in recipient BM, suggest that tissue-resident GvH-reactive donor T cells migrated into the recipient circulation and BM, where they destroyed recipient hematopoietic cells through cytolytic effector functions and promoted engraftment of graft-derived HSPCs that maintain chimerism. These mechanisms suggest an approach to achieving intestinal allograft tolerance.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Intestinos/transplante , Linfopoese/imunologia , Transplante de Órgãos , Linfócitos T/imunologia , Quimeras de Transplante/imunologia , Aloenxertos , Feminino , Doença Enxerto-Hospedeiro/patologia , Humanos , Intestinos/imunologia , Intestinos/patologia , Masculino , Linfócitos T/patologia
3.
J Immunother Cancer ; 8(2)2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32690771

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is notoriously resistant to treatment including checkpoint-blockade immunotherapy. We hypothesized that a bimodal treatment approach consisting of dendritic cell (DC) vaccination to prime tumor-specific T cells, and a strategy to reprogram the desmoplastic tumor microenvironment (TME) would be needed to break tolerance to these pancreatic cancers. As a proof-of-concept, we investigated the efficacy of combined DC vaccination with CD40-agonistic antibodies in a poorly immunogenic murine model of PDAC. Based on the rationale that mesothelioma and pancreatic cancer share a number of tumor associated antigens, the DCs were loaded with either pancreatic or mesothelioma tumor lysates. METHODS: Immune-competent mice with subcutaneously or orthotopically growing KrasG12D/+;Trp53R172H/+;Pdx-1-Cre (KPC) PDAC tumors were vaccinated with syngeneic bone marrow-derived DCs loaded with either pancreatic cancer (KPC) or mesothelioma (AE17) lysate and consequently treated with FGK45 (CD40 agonist). Tumor progression was monitored and immune responses in TME and lymphoid organs were analyzed using multicolor flow cytometry and NanoString analyzes. RESULTS: Mesothelioma-lysate loaded DCs generated cross-reactive tumor-antigen-specific T-cell responses to pancreatic cancer and induced delayed tumor outgrowth when provided as prophylactic vaccine. In established disease, combination with stimulating CD40 antibody was necessary to improve survival, while anti-CD40 alone was ineffective. Extensive analysis of the TME showed that anti-CD40 monotherapy did improve CD8 +T cell infiltration, but these essential effector cells displayed hallmarks of exhaustion, including PD-1, TIM-3 and NKG2A. Combination therapy induced a strong change in tumor transcriptome and mitigated the expression of inhibitory markers on CD8 +T cells. CONCLUSION: These results demonstrate the potency of DC therapy in combination with CD40-stimulation for the treatment of pancreatic cancer and provide directions for near future clinical trials.


Assuntos
Adenocarcinoma/terapia , Vacinas Anticâncer/uso terapêutico , Carcinoma Ductal Pancreático/terapia , Células Dendríticas/metabolismo , Adenocarcinoma/patologia , Animais , Vacinas Anticâncer/farmacologia , Carcinoma Ductal Pancreático/patologia , Modelos Animais de Doenças , Feminino , Humanos , Camundongos
4.
Cancer Cell ; 38(5): 685-700.e8, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33007259

RESUMO

PD-1/PD-L1-checkpoint blockade therapy is generally thought to relieve tumor cell-mediated suppression in the tumor microenvironment but PD-L1 is also expressed on non-tumor macrophages and conventional dendritic cells (cDCs). Here we show in mouse tumor models that tumor-draining lymph nodes (TDLNs) are enriched for tumor-specific PD-1+ T cells which closely associate with PD-L1+ cDCs. TDLN-targeted PD-L1-blockade induces enhanced anti-tumor T cell immunity by seeding the tumor site with progenitor-exhausted T cells, resulting in improved tumor control. Moreover, we show that abundant PD-1/PD-L1-interactions in TDLNs of nonmetastatic melanoma patients, but not those in corresponding tumors, associate with early distant disease recurrence. These findings point at a critical role for PD-L1 expression in TDLNs in governing systemic anti-tumor immunity, identifying high-risk patient groups amendable to adjuvant PD-1/PD-L1-blockade therapy.


Assuntos
Antígeno B7-H1/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Linfonodos/imunologia , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/imunologia , Adulto , Animais , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular Tumoral , Células Dendríticas/imunologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfonodos/efeitos dos fármacos , Masculino , Melanoma/imunologia , Melanoma/patologia , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Linfócitos T/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Cell Stem Cell ; 24(2): 227-239.e8, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30503142

RESUMO

Human intestinal transplantation often results in long-term mixed chimerism of donor and recipient blood in transplant patients. We followed the phenotypes of chimeric peripheral blood cells in 21 patients receiving intestinal allografts over 5 years. Donor lymphocyte phenotypes suggested a contribution of hematopoietic stem and progenitor cells (HSPCs) from the graft. Surprisingly, we detected donor-derived HSPCs in intestinal mucosa, Peyer's patches, mesenteric lymph nodes, and liver. Human gut HSPCs are phenotypically similar to bone marrow HSPCs and have multilineage differentiation potential in vitro and in vivo. Analysis of circulating post-transplant donor T cells suggests that they undergo selection in recipient lymphoid organs to acquire immune tolerance. Our longitudinal study of human HSPCs carried in intestinal allografts demonstrates their turnover kinetics and gradual replacement of donor-derived HSPCs from a circulating pool. Thus, we have demonstrated the existence of functioning HSPCs in human intestines with implications for promoting tolerance in transplant recipients.


Assuntos
Movimento Celular , Células-Tronco Hematopoéticas/citologia , Intestinos/citologia , Intestinos/transplante , Animais , Diferenciação Celular , Linhagem Celular , Linhagem da Célula , Quimerismo , Doença Enxerto-Hospedeiro/imunologia , Humanos , Tolerância Imunológica , Mucosa Intestinal/citologia , Fígado/citologia , Linfonodos/citologia , Camundongos , Nódulos Linfáticos Agregados/citologia , Fenótipo , Linfócitos T/citologia , Doadores de Tecidos , Transplante Homólogo
6.
JCI Insight ; 3(15)2018 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-30089728

RESUMO

Alloreactive T lymphocytes are the primary mediators of immune responses in transplantation, both in the graft-versus-host and host-versus-graft directions. While essentially all clones comprising the human T cell repertoire have been selected on self-peptide presented by self-human leukocyte antigens (self-HLAs), much remains to be understood about the nature of clones capable of responding to allo-HLA molecules. Quantitative tools to study these cells are critical to understand fundamental features of this important response; however, the large size and diversity of the alloreactive T cell repertoire in humans presents a great technical challenge. We have developed a high-throughput T cell receptor (TCR) sequencing approach to characterize the human alloresponse. We present a statistical method to model T cell clonal frequency distribution and quantify repertoire diversity. Using these approaches, we measured the diversity and frequency of distinct alloreactive CD4+ and CD8+ T cell populations in HLA-mismatched responder-stimulator pairs. Our findings indicate that the alloimmune repertoire is highly specific for a given pair of individuals, that most alloreactive clones circulate at low frequencies, and that a high proportion of TCRs is likely able to recognize alloantigens.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Antígenos HLA/imunologia , Isoantígenos/imunologia , Linfócitos T/imunologia , Adulto , Transplante de Medula Óssea/efeitos adversos , Simulação por Computador , Voluntários Saudáveis , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunofenotipagem , Transplante de Rim/efeitos adversos , Modelos Biológicos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Transplante Homólogo/efeitos adversos
7.
Cytokine Growth Factor Rev ; 36: 5-15, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28693973

RESUMO

With the widespread application of immune checkpoint blocking antibodies (ICBs) for the treatment of advanced cancer, immunotherapy has proven to be capable of yielding unparalleled clinical results. However, despite the initial success of ICB-treatment, still a minority of patients experience durable responses to ICB therapy. A plethora of mechanisms underlie ICB resistance ranging from low immunogenicity, inadequate generation or recruitment of tumor-specific T cells or local suppression by stromal cells to acquired genetic alterations leading to immune escape. Increasing the response rates to ICBs requires insight into the mechanisms underlying resistance and the subsequent design of rational therapeutic combinations on a per patient basis. In this review, we aim to establish order into the mechanisms governing primary and secondary ICB resistance, offer therapeutic options to circumvent different modes of resistance and plea for a personalized medicine approach to maximize immunotherapeutic benefit for all cancer patients.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Imunoterapia/métodos , Neoplasias/terapia , Linfócitos T/imunologia , Animais , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Antígeno CTLA-4/metabolismo , Humanos , Imunoterapia/tendências , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Medicina de Precisão , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Microambiente Tumoral
8.
Sci Immunol ; 1(4)2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28239678

RESUMO

A paradigm in transplantation states that graft-infiltrating T cells are largely non-alloreactive "bystander" cells. However, the origin and specificity of allograft T cells over time has not been investigated in detail in animals or humans. Here, we use polychromatic flow cytometry and high throughput TCR sequencing of serial biopsies to show that gut-resident T cell turnover kinetics in human intestinal allografts are correlated with the balance between intra-graft host-vs-graft (HvG) and graft-vs-host (GvH) reactivities and with clinical outcomes. In the absence of rejection, donor T cells were enriched for GvH-reactive clones that persisted long-term in the graft. Early expansion of GvH clones in the graft correlated with rapid replacement of donor APCs by the recipient. Rejection was associated with transient infiltration by blood-like recipient CD28+ NKG2DHi CD8+ alpha beta T cells, marked predominance of HvG clones, and accelerated T cell turnover in the graft. Ultimately, these recipient T cells acquired a steady state tissue-resident phenotype, but regained CD28 expression during rejections. Increased ratios of GvH to HvG clones were seen in non-rejectors, potentially mitigating the constant threat of rejection posed by HvG clones persisting within the tissue-resident graft T cell population.

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