Preclinical models have shown that blocking PD-1/PD-L1 pathways enhances antileukemic responses. Azacitidine upregulates PD-1 and IFNγ signaling. We therefore conducted this single-arm trial, in ...which patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were treated with azacitidine 75 mg/m
days 1 to 7 intravenously or subcutaneously with nivolumab 3 mg/kg intravenously on days 1 and 14, every 4 to 6 weeks. For the seventy patients who were treated, the median age was 70 years (range, 22-90) and the median number of prior therapies received was 2 (range, 1-7). The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)-naïve (
= 25) and HMA-pretreated (
= 45) patients, respectively. Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA4 was significantly upregulated on CD4
Teff in nonresponders after 2 and 4 doses of nivolumab. Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection. SIGNIFICANCE: Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-naïve, or had increased pretherapy CD3
bone marrow infiltrate by flow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials.
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Typical injection schemes of rotating detonation combustors inject fuel locally into the combustion channel, creating stratified fuel-rich and fuel-lean mixing regions. In this study, premixed ...hydrogen and air rotating detonations are explored in a rotating detonation combustor through premixing part of the fuel into the oxidizer flow. The objective is to investigate the effect of premixing on the operation of the combustor. Three premixing schemes are examined where the detonation wave speeds are analyzed. The results show that in premixing, the fuel-lean regions became more favorable for continuous detonation propagation when premixed with the bypass fuel, resulting in higher detonation wave speeds. This phenomenon is shown to be independent of the global fuel-air equivalence ratio and the amount of fuel premixed into the oxidizer. As such, combustor performance and the operational regime could be improved with lean hydrogen premixing amounts in the main flow oxidizer.
•Premixed H2 and air rotating detonations are explored in a rotating detonation combustor (RDC).•Lean hydrogen premixing enhances detonation wave propagation velocity performance.•The wave speed increase is independent of the level of premixing in the oxidizer stream.•A low level of premixing results in enhanced performance and expanded RDC operability.
Se identifican los fundamentos filosóficos de la educación intercultural bilingüe. Luego se contrastan cuáles de estos fundamentos filosóficos, están considerados en la propuesta de Educación ...Intercultural Bilingüe para la región Junín. Se empleó el método hermenéutico, el que permitió hacer un análisis de los fundamentos epistémicos que subyacen en la filosofía de la interculturalidad. Para concluir que: los fundamentos filosóficos interculturales, en la educación intercultural de la región Junín, son imprecisos y elementales.
•Demonstrated multiphase rotating detonation waves with carbon particles in a Rotating Detonation Engine.•Evidence of carbon driven rotating waves are experimentally shown through detonability and ...wave speed.•Heat of combustion correlates to the carbon concentration and the wave speed at fixed equivalence ratio.•Mechanisms of the carbon particle shock interaction and subsequent reactions are presented.
Coal dust explosions can be hazardous; however, they can also generate a significant rise in stagnation pressure if adequately harnessed. Rotating detonation combustors seek to take advantage of the stagnation pressure rise phenomenon in a more sustained and controlled manner via confinement to a physical annulus, leading to increased overall thermodynamic efficiency. This investigation presents an analysis of detonations fueled by Carbon Black, a solid particulate consisting of virtually pure carbon molecules and lean Hydrogen-Air mixtures. It is realized that with the addition of Carbon Black, an increase of lean mixture detonability and detonation velocities extending the operating limit over that of a pure hydrogen-air mixture is experienced. For all testing conditions, the total equivalence ratio is held at φ = 1, while the fuel mixture's carbon mass fraction is increased from 0 to 0.7 while the hydrogen is decreased. Detonation wave velocities are extracted from high-speed imaging through applying a Discrete Fourier Transform algorithm to determine changes to the wave speed as Carbon Black particles are introduced. As a result, due to the addition of Carbon Black as an auxiliary fuel source, detonations were formed instead of deflagrations in operating conditions where one would expect deflagrations at the same hydrogen-air equivalence ratios without Carbon Black addition. The detonation formation provides evidence that the coal particles are reacting within the detonation wave in a large enough capacity to support a detonation wave within the annulus. Furthermore, the wave speed is shown to increase with the additional of carbon particles. At a constant global equivalence ratio, the detonation wave velocities were found to decrease with hydrogen's incremental replacement with coal particles. Whereby, through a theoretical comparison of the heat of combustion as computed from the experimentally derived detonation wave velocities, a linear relationship of the two was shown to exist. Therefore, the heat of combustion has the potential to describe an operational limit to sustaining a detonation wave.
Background
Phenotypic characterization of immune cells in the bone marrow (BM) of patients with acute myeloid leukemia (AML) is lacking.
Methods
T‐cell infiltration was quantified on BM biopsies from ...13 patients with AML, and flow cytometry was performed on BM aspirates (BMAs) from 107 patients with AML who received treatment at The University of Texas MD Anderson Cancer Center. The authors evaluated the expression of inhibitory receptors (programmed cell death protein 1 PD1, cytotoxic T‐lymphocyte antigen 4 CTLA4, lymphocyte‐activation gene 3 LAG3, T‐cell immunoglobulin and mucin‐domain containing‐3 TIM3) and stimulatory receptors (glucocorticoid‐induced tumor necrosis factor receptor‐related protein GITR, OX40, 41BB a type 2 transmembrane glycoprotein receptor, inducible T‐cell costimulatory ICOS) on T‐cell subsets and the expression of their ligands (41BBL, B7‐1, B7‐2, ICOSL, PD‐L1, PD‐L2, and OX40L) on AML blasts. Expression of these markers was correlated with patient age, karyotype, baseline next‐generation sequencing for 28 myeloid‐associated genes (including P53), and DNA methylation proteins (DNA methyltransferase 3α, isocitrate dehydrogenase 1IDH1, IDH2, Tet methylcytosine dioxygenase 2 TET2, and Fms‐related tyrosine kinase 3 FLT3).
Results
On histochemistry evaluation, the T‐cell population in BM appeared to be preserved in patients who had AML compared with healthy donors. The proportion of T‐regulatory cells (Tregs) in BMAs was higher in patients with AML than in healthy donors. PD1‐positive/OX40‐positive T cells were more frequent in AML BMAs, and a higher frequency of PD1‐positive/cluster of differentiation 8 (CD8)‐positive T cells coexpressed TIM3 or LAG3. PD1‐positive/CD8‐positive T cells were more frequent in BMAs from patients who had multiply relapsed AML than in BMAs from those who had first relapsed or newly diagnosed AML. Blasts in BMAs from patients who had TP53‐mutated AML were more frequently positive for PD‐L1.
Conclusions
The preserved T‐cell population, the increased frequency of regulatory T cells, and the expression of targetable immune receptors in AML BMAs suggest a role for T‐cell–harnessing therapies in AML.
T‐cell subsets are preserved in the bone marrow of patients with acute myeloid leukemia. The expression of targetable immune checkpoints by T cells suggests that therapies harnessing T cells may benefit these patients.
Coal dust explosions can be hazardous; however, they can also generate a significant rise in stagnation pressure if adequately harnessed. Rotating detonation combustors seek to take advantage of the ...stagnation pressure rise phenomenon in a more sustained and controlled manner via confinement to a physical annulus, leading to increased overall thermodynamic efficiency. Here this investigation presents an analysis of detonations fueled by Carbon Black, a solid particulate consisting of virtually pure carbon molecules and lean Hydrogen-Air mixtures. It is realized that with the addition of Carbon Black, an increase of lean mixture detonability and detonation velocities extending the operating limit over that of a pure hydrogen-air mixture is experienced. For all testing conditions, the total equivalence ratio is held at φ = 1, while the fuel mixture's carbon mass fraction is increased from 0 to 0.7 while the hydrogen is decreased. Detonation wave velocities are extracted from high-speed imaging through applying a Discrete Fourier Transform algorithm to determine changes to the wave speed as Carbon Black particles are introduced. As a result, due to the addition of Carbon Black as an auxiliary fuel source, detonations were formed instead of deflagrations in operating conditions where one would expect deflagrations at the same hydrogen-air equivalence ratios without Carbon Black addition. The detonation formation provides evidence that the coal particles are reacting within the detonation wave in a large enough capacity to support a detonation wave within the annulus. Furthermore, the wave speed is shown to increase with the additional of carbon particles. At a constant global equivalence ratio, the detonation wave velocities were found to decrease with hydrogen's incremental replacement with coal particles. Whereby, through a theoretical comparison of the heat of combustion as computed from the experimentally derived detonation wave velocities, a linear relationship of the two was shown to exist. Therefore, the heat of combustion has the potential to describe an operational limit to sustaining a detonation wave.
Outcomes for younger patients with acute myeloid leukaemia have moderately improved over the past two decades owing to better supportive care and recent introduction of novel targeted agents. ...Blocking PD-1 and its ligand's pathways enhances antileukaemia responses by enabling T cells in murine models. We aimed to assess the addition of nivolumab to frontline therapy with idarubicin and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome.
This single-arm, phase 2 part of the phase 1-2 study of nivolumab in combination with idarubicin and cytarabine was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients were aged 18-60 years (or >60 years if suitable for intensive chemotherapy), and had newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, and an Eastern Cooperative Oncology Group performance status of 0-2. Induction included cytarabine 1·5 g/m
by 24-h continuous infusion daily on days 1-4 (3 days in patients >60 years) and idarubicin 12 mg/m
daily on days 1-3. Nivolumab 3 mg/kg was started on day 24 (range 22-26) and continued every 2 weeks for up to a year in responders. Responders received either up to five consolidation cycles of attenuated doses of idarubicin and cytarabine, or allogeneic stem cell transplantation if eligible. The primary endpoint was event-free survival. Efficacy and safety analyses were done in all patients who received at least one dose of study treatment. Secondary endpoints were relapse-free survival and overall survival. This ongoing trial is registered with ClinicalTrials.gov, number NCT02464657.
Between Aug 7, 2015, and June 2, 2018, 44 patients were enrolled of whom 22 (50%) had adverse genetic risk by European Leukaemia Network classification. All patients were evaluable for safety and efficacy. At a median follow-up of 17·25 months (IQR 0·50-30·40), median event-free survival was not reached (95% CI 7·93-NR). Median relapse-free survival of responders was 18·54 months (95% CI 8·20-23·22). The median overall survival was 18·54 months (95% CI 10·81-28·81). Six patients had seven grade 3-4 immune-related adverse events with two cases of rash, two of colitis, and one each of transaminitis, pancreatitis, and cholecystitis. 19 (43%) of 44 patients achieved a response and proceeded to allogeneic stem cell transplantation, with grade 3-4 graft-versus-host disease observed in five (26%). No treatment related deaths were attributed to nivolumab.
Addition of nivolumab to induction chemotherapy with idarubicin and cytarabine is feasible in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome. Post-transplant severe graft-versus-host disease could be improved, and earlier initiation of checkpoint inhibitor therapy is warranted in future studies.
The MD Anderson Cancer Center Support Grant CA016672, and the MD Anderson Cancer Center Leukaemia SPORE CA100632 from the National Cancer Institute, Bristol Myers Squibb.
Background
The combination of the αPD-1 (nivolumab) and hypomethylating agent azacytidine demonstrated encouraging response rate and overall survival in relapsed/refractory acute myeloid leukemia ...(AML) patients, compared to azacytidine alone1 (NCT02397720). However, the percentage of the patient who achieved an IWG 2016 response to such therapy was still limited (overall response rate = 33%), so it is desirable to have early predictive biomarkers to facilitate patient stratification and selection for future trials. A better understanding of T cells (primary targets of αPD-1 therapy) from bone marrow (BM) and peripheral blood (PB) in AML pre-therapy and on-therapy should yield valuable insights on the treatment-induced anti-tumor response.
Methods
We performed whole transcriptomic profiling (RNA-sequencing, RNA-seq) on T cells from a cohort of AML patients who were enrolled in the clinical trial mentioned above, and treated with azacytidine and nivolumab (Table 1). Sixty-four FACS-sorted patient-derived T cell samples from cryopreserved peripheral blood (PB) or bone marrow (BM) aspirates, which were collected pre-therapy (T0) and after the first round of treatment (end of cycle one, EOC1), were evaluated. By leveraging subset definitions based on scRNA-seq results from T cells of cancer patients, we implemented deconvolution of our bulk T-cell RNA-seq data to obtain the relative abundance of different T-cell subsets (in-silico dissection without physical isolation).
Results
We performed ex vivo cDNA library preparation on 2,000-100,000 sorted T cells and yielded a minimal of 17 million sequencing reads per BM T-cell library and 2.6 million sequencing reads per PBMC T-cell library. We compared the gene expression profile of peripheral blood T cells from AML patients (CD4: n = 16; CD8: n = 15) and healthy donors (HD, n = 8)2,3 to validate our methodology. The deconvolution results were consistent with previously published flow-cytometry data profiling cancer patients4,5 (Figure 1). In comparison with HDs, circulating CD4 T cells from AML patients consisted of a higher frequency of Treg (AML versus HD: 5.1% versus 0.6%, P<0.0001)4. Peripheral blood CD8 T cells from AML patients were with a significantly lower frequency of naïve (AML versus HD: 22.1% versus 55.9%, P<0.0001), a higher frequency of effector phenotype (AML versus HD: 35.6% versus 6.7%, P =0.0011), and an increasing frequency of exhausted phenotype (AML versus HD: 19.1% versus 0.0%, P<0.0001)5.
Independent of the clinical responses attained on the azacytidine and nivolumab, comparison of the pre-therapy CD8 T cells from BM and PB from all AML patients using both gene set enrichment analysis and deconvolution indicated that the BM CD8 T cells were more activated/differentiated compared with PBMC CD8 T cells, likely reflective of an ongoing immune response against the AML. We also found treatment-induced gene expression profile changes in the AML circulating CD8 T cells, characterized by increased cell metabolism and cell proliferation. Deconvolution identified that pre-therapy relative abundance of exhausted (CD3+CD8+PD-1+CD45RO+) and effector (CD3+CD8+CD45RA+Tbet+PD-1lo) CD8 T cells (plasticity) could serve as subpopulations relevant for patient stratification (Figure 2). We further validated these results using CyTOF wherein these same subpopulations were differentially abundant between responders and non-responders at the pre-therapy time-point.
Conclusions
Collectively, the analyses of RNA-seq of CD8 T cells from AML patients on the azacytidine with nivolumab trial revealed that (1) the PD-1 blockade-based treatment-induced gene expression profiling changes (increased cell proliferation and metabolism) of CD8 T cells are detectable as early as EOC1 in the peripheral blood; (2) specific subpopulations of plastic CD8 T cells identified may have the potential to serve as an actionable biomarker to select AML patients most likely to benefit from such immune checkpoint therapies. These findings need to be confirmed in larger studies, planned or currently being conducted, with αPD-1 based therapies in AML and MDS.
References
1. Daver, N. et al. Cancer Discov.9, 370-383 (2019).
2. Corces, M. R. et al. Nat. Genet.48, 1193-1203 (2016).
3. Linsley, P. S. et al. PLoS One9, (2014).
4. Szczepanski, M. J. et al. Clin. Cancer Res.15, 3325-3332 (2009).
5. Knaus, H. A. et al. JCI Insight3, (2018).
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Varadarajan:CellChorus: Employment, Equity Ownership.
Reverse transcription polymerase chain reaction (RT‐PCR) for BCR::ABL1 is the most common and widely accepted method of measurable residual disease (MRD) assessment in Philadelphia ...chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL); however, RT‐PCR may not be an optimal measure of MRD in many cases of Ph+ ALL. We evaluated the clinical impact of a highly sensitive next‐generation sequencing (NGS) MRD assay (sensitivity of 10−6) and its correlation with RT‐PCR for BCR::ABL1 in patients with Ph+ ALL. Overall, 32% of patients had a discordance between MRD assessment by RT‐PCR and NGS, and 31% of patients who achieved NGS MRD negativity were PCR+ at the same timepoint. Among eight patients with long‐term detectable BCR::ABL1 by PCR, six were PCR+/NGS−. These patients generally had stable PCR levels that persisted despite therapeutic interventions, and none subsequently relapsed; in contrast, patients who were PCR+/NGS+ had more variable PCR values that responded to therapeutic intervention. In a separate cohort of prospectively collected clinical samples, 11 of 65 patients (17%) with Ph+ ALL who achieved NGS MRD negativity had detectable BCR::ABL1 by PCR, and none of these patients relapsed. Relapse‐free survival and overall survival were similar in patients who were PCR+/NGS− and PCR−/NGS−, suggesting that PCR for BCR::ABL1 did not provide additional prognostic information in patients who achieved NGS MRD negativity. NGS‐based assessment of MRD is prognostic in Ph+ ALL and identifies patients with low‐level detectable BCR::ABL1 who are unlikely to relapse nor to benefit from therapeutic interventions.
Highly sensitvie NGS‐based assessment of MRD is prognostic in Ph+ ALL and identifies patients with low‐level detectable BCR::ABL1 who are unlikely to relapse nor to benefit from therapeutic interventions.
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