2: Donor-Recipient Host-Versus-Graft Human Leukocyte Antigen Mismatches and Outcome of Cord Blood Transplants

Digitalitzat per Artypla

Safety, tolerability, and potential clinical activity of a glucocorticoid-induced TNF receptor-related protein agonist alone or in combination with nivolumab for patients with advanced solid tumors: a phase 1/2a dose-escalation and cohort-expansion clinical trial

Importance: Multiple immunostimulatory agonist antibodies have been clinically tested in solid tumors to evaluate the role of targeting glucocorticoid-induced tumor necrosis factor (TNF) receptor-related protein in anticancer treatments. Objective: To evaluate the safety and activity of the fully human glucocorticoid-induced TNF receptor-related protein agonist IgG1 monoclonal antibody BMS-986156 with or without nivolumab in patients with advanced solid tumors. Design, Setting, and Participants: This global, open-label, phase 1/2a study of BMS-986156 with or without nivolumab enrolled 292 patients 18 years or older with advanced solid tumors and an Eastern Cooperative Oncology Group performance status of 1 or less. Prior checkpoint inhibitor therapy was allowed. Monotherapy and combination dose-escalation cohorts ran concurrently to guide expansion doses beginning October 16, 2015; the study is ongoing. Interventions: The protein agonist BMS-986156 was administered intravenously at a dose of 10, 30, 100, 240, or 800 mg every 2 weeks as monotherapy, and in the combination group 30, 100, 240, or 800 mg plus 240 mg of nivolumab every 2 weeks; same-dose cohorts were pooled for analysis. One cohort also received 480 mg of BMS-986156 plus 480 mg of nivolumab every 4 weeks. Main Outcomes and Measures: The primary end points were safety, tolerability, and dose-limiting toxic effects. Additional end points included antitumor activity per Response Evaluation Criteria in Solid Tumors, version 1.1, and exploratory biomarker analyses. Results: With a follow-up range of 1.4 to 101.7 weeks (follow-up ongoing), 34 patients (16 women and 18 men; median age, 56.6 years [range, 28-75 years]) received monotherapy (4 patients completed initial treatment), and 258 patients (140 women and 118 men; median age, 60 years [range, 21-87 years]) received combination therapy (65 patients completed initial treatment). No grade 3 to 5 treatment-related adverse events occurred with BMS-986156 monotherapy; grade 3 to 4 treatment-related adverse events occurred in 24 patients (9.3%) receiving BMS-986156 plus nivolumab, with no grade 5 treatment-related adverse events. One dose-limiting toxic effect (grade 4 elevated creatine phosphokinase levels) occurred in a patient receiving 800 mg of BMS-986156 plus 240 mg of nivolumab every 2 weeks; BMS-986156 with or without nivolumab exhibited linear pharmacokinetics with dose-related increase after a single dose. Peripheral T-cell and natural killer-cell proliferation increased after administration of BMS-986156 with or without nivolumab. No consistent and significant modulation of intratumoral CD8+ T cells and FoxP3+ regulatory T cells was observed. No responses were seen with BMS-986156 alone; objective response rates ranged from 0% to 11.1% (1 of 9) across combination therapy cohorts, with a few responses observed in patients previously treated with anti-programmed death receptor (ligand) 1 therapy. Conclusions and Relevance: Based on this cohort, BMS-986156 appears to have had a manageable safety profile, and BMS-986156 plus nivolumab demonstrated safety and efficacy comparable to historical data reported for nivolumab monotherapy. Trial Registration: ClinicalTrials.gov identifier: NCT02598960

Analysis of immunophenotypic profile of NK cells and correlation to PD-­1 and PD-­L1 expression in HIV-­infected individuals

A evolução do conhecimento sobre o HIV e seus efeitos sobre as diferentes células do sistema imune possibilitaram a criação e o aperfeiçoamento de um grande arsenal terapêutico. Atualmente, a sobrevida de casos recém-­ diagnosticados é medida em décadas; entretanto, alguns pacientes não apresentam recuperação do sistema imune após a agressão inicial sofrida pelo vírus, a despeito de tratamento adequado. As células NK são identificadas como componentes da imunidade inata, responsáveis pelo combate a infecções virais e tumores. Elas são divididas em CD56dim e CD56hi, com diferentes capacidades citotóxicas e de produção de citocinas; uma terceira subpopulação composta por células CD56neg está presente em proporções mínimas em adultos saudáveis, porém tem maior importância em neonatos e está expandida em indivíduos cronicamente infectados pelo HIV, podendo ser identificada pelos marcadores CD7 e CD16. Dentre diversos outros, as células NK expressam receptores ativadores e inibitórios chamados KIR, que interagem com moléculas HLA, identificando células próprias e aquelas que reduzem sua expressão como mecanismo de escape imunológico; a interação entre KIR e HLA tem papel na evolução clínica da infecção por HIV/AIDS, particularmente envolvendo o receptor KIR3DL1. PD-­ 1 é um checkpoint do sistema imunológico que pode ter sua expressão aumentada em tumores e infecções virais crônicas. A expressão de PD-­1 em células T correlaciona-­se a marcadores prognósticos na infecção por HIV/AIDS; sua expressão em células NK já foi documentada, porém temos poucas informações a respeito. Este trabalho buscou detalhar a expressão de PD-­1 e seu ligante PD-­L1 em células NK e monócitos em participantes infectados pelo HIV e controles. Foram recrutados participantes diagnosticados e acompanhados desde a infecção aguda, participantes diagnosticados após um intervalo de tempo desconhecido desde a soroconversão e controles não infectados sob alto risco por exposição sexual. As amostras foram processadas a fresco no LIM-­60; PD-­1 e outros marcadores foram analisados por citometria de fluxo multicor. A expressão de PD-­1 em células NK correlacionou-­se a contagens de células T CD4+ e expressão de PD-­1 em células T nos participantes infectados; dentre estes, os participantes seguidos desde a infecção aguda tiveram menor expressão de PD-­1. Os participantes seguidos desde a infecção aguda tiveram ainda menor expressão de PD-­L1 em monócitos quando comparados aos participantes diagnosticados em fase desconhecida da doença, e também quando comparados aos controles não infectados. Houve aumento expressivo da proporção de células KIR3DL1+ entre as células CD56neg nos participantes infectados em comparação ao grupo não infectado. Concluímos que a expressão de PD-­1 em células NK está aumentada em pessoas infectadas pelo HIV e correlaciona-­se a outros parâmetros imunológicos, como contagem de células T CD4+ e expressão de PD-­1 em células T. A exaustão das células NK pode, portanto, contribuir para o dano imunológico causado pelo HIV e pode ser explorada como um alvo para novas modalidades terapêuticasThe expansion of our knowledge about the HIV and its effects on the entire immune system has led the development of a vast therapeutic arsenal. Survival for newly diagnosed cases is now measured in decades;? some patients, however, never recover full immune function following the initial aggression inflicted by HIV, despite adequate treatment. NK cells are identified as innate immunity components, responsible for fighting viral infections and tumors. They are separated in CD56dim and CD56hi cells, which present different cytotoxicity and cytokine production capacity. A third distinct subpopulation constituted by CD56neg cells can be found in minimal counts in healthy adults, but is present in newborns and is expanded in chronically HIV-­ infected subjects;? these cells can be identified as CD7+CD16+. Among others, NK cells express activating and inhibitory receptors called KIR, which interact with HLA molecules and identify \"self\" cells and cells that have downregulated its expression as an immunologic evasion strategy. Studies have documented the importance of KIR and HLA interaction in HIV/AIDS infection clinical course, particularly involving the receptor KIR3DL1. PD-­1 is an immune checkpoint that can be upregulated by tumors and chronic viral infections. PD-­ 1 expression on T cells is correlated to prognostic factors in HIV/AIDS infection; NK cells have been shown to express it, but further information is necessary. This study aimed at investigating PD-­1 and its ligand PD-­L1 expression on NK and monocytes in HIV-­infected participants and controls. We recruited a group of participants who were diagnosed during acute phase of HIV infection and have been followed ever since, a group of participants who were diagnosed after unknown interval since seroconversion, and a group of uninfected controls who have a high risk due to sexual exposure. Samples were freshly processed at LIM-­60; PD-­1 and other markers were analyzed by multicolor flow cytometry. We found PD-­1 expression on NK cells was correlated to T CD4+ cell counts and PD-­1 expression on T cells, in infected participants; among them, participants followed since acute infection expressed less PD-­1. They also expressed less PD-­L1 in monocytes, as compared to participants diagnosed after unknown interval since seroconversion, as well as compared to the uninfected group. We found significant increase in proportion of KIR3DL1-­expressing cells among CD56neg cells in infected participants compared to the uninfected group. We concluded that PD-­1 expression on NK cells is increased in people infected by HIV and correlated to other immunologic parameters such as T CD4+ counts and PD-­1 expression on T cells. NK cell exhaustion may, therefore, contribute to the immune damage induced by HIV-­1 infection and can be also explored as a target to find new ways to restore antiviral immunit

Donor-Recipient Host-Versus-Graft (HVG) HLA Mismatches and Outcome of Cord Blood Transplants (CBT)

Abstract The influence of HLA mismatches on outcomes of CBT is yet to be fully defined. We hypothesized that donor-recipient mismatches in the host-versus-graft (HVG) and graft-versus-host (GVH) direction impact engraftment, treatment-related mortality (TRM) and survival after CBT, and addressed the question studying CBT performed in our institution from 3/1996 to June/2006. Methods: 91 patients (pts) were analyzed. Diagnoses were high-risk hematologic malignancies (n=85; 93%) or non-malignant disorders (n=6; 7%). Conditioning was myeloablative (n=86; 95%), while patients not eligible for high-dose therapy received reduced-intensity (n=5; 5%) regimens. ATG was part of the preparative regimen in 45 cases (49%). GVHD prophylaxis was tacrolimus with (n=83; 91%) or without methotrexate (n=6; 6%), and cyclosporine and MMF (n=2; 2%). Grafts were single (n=70; 77%) or double (n=21; 23%) CB units. 9 pts received ex-vivo expanded grafts. For patients receiving a double CBT, the engrafted unit was used as the reference for this analysis. HLA-A, B (intermediate resolution) and DRB1 typing (high-resolution) was available for all donor-recipient pairs. Results: Median age was 18 years (1–57); 46 (51%) were younger than 18 yrs old and 50 pts (55%) were males. The patients were heavily pre-treated with 18 (20%) having received prior autotransplants. Disease status at CBT was complete remission (CR; n=43; 47%) and active disease (n=48; 53%). Median number of infused total nucleated cell was 3.45x10E7/kg (0.81–23.6). Numbers of mismatches in the HVG direction were as follows: zero (n=11), 1 (n=37), 2 (n=36), 3 (n=6), and 4 (n=1). Numbers of mismatches in the GVH direction were as follows: zero (n=8), 1 (n=35), 2 (n=41), and 3 (n=7). 78 pts engrafted neutrophils (86%) at a median of 22 days (4–60). 65 pts engrafted platelets (71%) at a median of 42 days(0–133). 13 pts (14%) failed to engraft. Grade II–IV and III–IV acute GVHD rates were 49% and 8%, respectively, and chronic GVHD incidence was 33%. 35 pts are alive with a median follow-up of 25 months. 2-yr actuarial survival is 21%. 100-day and 1-yr NRM is 22%(14–32) and 37% (28–49). The influence of HVG mismatches on NRM, survival and engraftment is shown in the table and figure. The decreasing 2-yr survival and worse NRM associated with increasing number of HVG mismatches was limited to the group of pts <18 yrs old. There was no difference in the proportion of pts in CR, nor in the distribution of infused TNC/Kg across the HVG mismatch subgroups. There was no correlation between mismatches in the GVH direction and NRM or 2-yr survival. Conclusion: HVG mismatches may influence outcomes of CBT. Number of Mismatches - HVG direction 1-yr NRM % engrafted Abbreviations: HVG: host-versus-graft; NRM: non-relapse mortality; NS: not significant 0 n=11 21% (CI: 6–74) 100 1 n=36 33% (CI: 20–54) 89 2 n=34 47% (CI: 33–67) 85 3 n=6 33% (CI: 11–100) P=NS 83 Figure Figur

Impact of hepatitis C virus seropositivity on survival after allogeneic hematopoietic stem cell transplantation for hematologic malignancies

The findings of this study suggest that hepatitis C seropositivity is a significant risk factor for non-relapse mortality after allogeneic stem cell transplantation, even in patients with normal or minimally abnormal liver function tests. See related perspective article on page 170