CTIM-21. AN AGE-SPECIFIC BIOMARKER IN NEWLY-DIAGNOSED GLIOBLASTOMA PATIENTS TREATED WITH RADIATION, NIVOLUMAB AND BMS-986205

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi54-vi54
Author(s):  
Miri Kim ◽  
Erik Ladomersky ◽  
Lijie Zhai ◽  
Lakshmi Bollu ◽  
April Bell ◽  
...  

Abstract INTRODUCTION We previously determined that advanced age plays a negative role in the survival outcome of human recurrent glioblastoma (GBM) patients treated with immune checkpoint blockade. Here we investigate the immunologic “signature” of younger patients who are < 65 years of age and older adult GBM patients who are ≥ 65 years of age that undergo simultaneous treatment with standard radiation, nivolumab (anti-PD-1 mAb), and BMS-986205 (a potent IDO enzyme inhibitor) and are newly diagnosed with O6-methylguanine-DNA methyl-transferase (MGMT) unmethylated GBM. Our objective was to identify age-dependent immunologic changes before and after treatment with immunotherapy. METHODS Patients ≥ 18 years old with newly diagnosed MGMT unmethylated GBM, KPS ≥ 70, and minimal steroid use were eligible for enrollment in this phase 1 trial. PBMCs and serum were drawn at baseline and routine post-treatment time points followed by mass spec analysis of kynurenine (Kyn) and tryptophan (Trp) metabolites, RNAseq, and 18-color flow cytometric analysis. RESULTS 8 younger adults with a median age of 50 years old and 4 older adults with a median age of 68.5 years old were studied. The median overall survival of younger and older adults was 368 and 108.5 days, respectively (p=0.032, HR 4.8 for age). BMS-986205 treatment decreased the Kyn/Trp ratio of all patients irrespective of age. RNAseq analysis found significant age-related changes using Gene Ontology pathway analysis of T cell related immunity, lymphocyte activation, and NK cell mediated immunity. Flow cytometric analysis is ongoing. CONCLUSIONS Similar to what was reported in older adult mice treated with simultaneous RT, anti-PD-1 mAb, and IDO enzyme inhibitor, advanced age negatively affected the survival in older adult human GBM patients treated with an analogous clinical approach. Future determination of whether the age-related biomarker profile can be used diagnostically and therapeutically is now under investigation.

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi97-vi97
Author(s):  
Erik Ladomersky ◽  
Lijie Zhai ◽  
Lakshmi Bollu ◽  
April Bell ◽  
Kristen Lauing ◽  
...  

Abstract Wild-type IDH glioblastoma (wtGBM) represents ≥90% of human GBM patient diagnoses with a median age of onset at 68-70 years of age. We previously found a decline of GBM patient survival with progressive age and that subjects ≥65 years of age had the poorest prognosis. We also showed an age-dependent enhancement of immune suppression in the brain that negatively affected immunotherapeutic efficacy in older adult mice with syngeneic brain tumors. Here, we extended those observations while studying C57BL/6 mice with intracranial CT-2A or GL261 between 80-110 weeks old - analogous to the age of a wtIDH GBM patient diagnosis. Overall survival of older adult mice with CT-2A or GL261 was significantly decreased when subjects were lymphopenic for CD4+ T cells as compared to an IgG Ab treatment group (n=12/group; p< 0.01). CD8+ T cell or NK cell leukopenia had no effect on survival outcomes. The negative effect of CD4+ T cell lymphopenia in older adults was not observed in younger mice with brain tumors. We also investigated the increased immunosuppression in the brain and its relationship to the accumulation of senescent cells and the treatment with standard of care radiation/temozolomide (RT/TMZ). p16INK4A, a marker for senescent cells, was increased in non-tumor cells of the brain during advanced age and its expression was increased after treatment with RT/TMZ. Older adult mice with brain tumors and treated with senolytics showed decreased p16INK4A levels after treatment with RT/TMZ. Senolytic treatment also improved the efficacy of combination therapy with RT, anti-PD-1 mAb, and IDO enzyme inhibitor in older adults as compared to senolytics alone or the triple immunotherapeutic cocktail alone (n=12-15/group; p< 0.01). Collectively, the results suggest that strategies aimed at reversing the effects of the aging combined with tumor eradication therapies may be particularly beneficial for older adult human patients with GBM.


2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii113-ii113
Author(s):  
Erik Ladomersky ◽  
Lijie Zhai ◽  
Lakshmi Bollu ◽  
April Bell ◽  
Kristen Lauing ◽  
...  

Abstract De novo glioblastoma (GBM) represents ≥ 90% of all GBM diagnoses and has a median age of onset at 65 years old. Because of its preponderance during advanced age, we investigated the mortality rate of older adult C57BL/6 (WT) mice with CT-2A glioma. Strikingly, we discovered a significant decrease of overall survival among animal subjects depleted for both CD4+ and CD8+ T cells as compared to the group treated with IgG control antibodies. This negative effect of lymphopenia only applied to older adults. We next questioned which of the major T cell subsets contribute to this effect and determined that the depletion of CD4+ T cells significantly decreased overall survival as compared to IgG control or CD8+ T cell-depleting antibodies (n=12/group; p< 0.01). We previously found increased immunosuppressive IDO levels in the mouse and human brain during advanced age. Although 78–86 week old WT mice have no survival benefit after triple combination immunotherapy, age-matched IDOKO mice have an impressive increase in median and overall survival – despite both groups being treated with a pharmacologic IDO enzyme inhibitor. Since IDO is potently-induced by proinflammatory cytokines, we hypothesized that a potential mechanism for the increased IDO during advanced age is associated with an accumulation of senescent cells in the brain with a proinflammatory secretory phenotype. To investigate this, 80 week old mice with intracranial GL261 were treated with (i) vehicle with IgG antibodies, (ii) the senolytic drugs dasatanib and quercetin, (iii) whole brain radiation, anti-PD-1 mAb, and IDO enzyme inhibitor, or (iv) the 5 agent combination. Only animal subjects treated with the 5 agent cocktail showed a significant increase in long-term survival in a subset of mice (n=12–15/group; p< 0.01). These results suggest that optimization of senescent cell eradication treatment may be particularly beneficial to older patients with GBM treated with immunotherapy.


Author(s):  
Zachary R Hettinger ◽  
Kyoko Hamagata ◽  
Amy L Confides ◽  
Marcus M Lawrence ◽  
Benjamin F Miller ◽  
...  

Abstract The inability to fully recover lost muscle mass following periods of disuse atrophy predisposes older adults to lost independence and poor quality of life. We have previously shown that mechanotherapy at a moderate load (4.5 N) enhances muscle mass recovery following atrophy in adult, but not older adult rats. We propose that elevated transverse stiffness in aged muscle inhibits the growth response to mechanotherapy and hypothesize that a higher load (7.6 N) will overcome this resistance to mechanical stimuli. F344/BN adult and older adult male rats underwent 14-days of hindlimb suspension, followed by 7-days of recovery with (RE+M) or without (RE) mechanotherapy at 7.6 N on gastrocnemius muscle. The 7.6 N load was determined by measuring transverse passive stiffness and linearly scaling up from 4.5 N. No differences in protein turnover or mean fiber cross sectional area were observed between RE and RE+M for older adult rats or adult rats at 7.6 N. However, there was a higher number of small muscle fibers present in older adult, but not adult rats, which was explained by a 16-fold increase in the frequency of small fibers expressing embryonic myosin heavy chain. Elevated central nucleation, satellite cell abundance, and dystrophin -/laminin + fibers were present in older adult rats only following 7.6 N, while 4.5 N did not induce damage at either age. We conclude that age is an important variable when considering load used during mechanotherapy and age-related transverse stiffness may predispose older adults to damage during the recovery period following disuse atrophy.


1995 ◽  
Vol 14 (6) ◽  
pp. 425-433 ◽  
Author(s):  
Xiao-Chun Wang ◽  
Kazumi Norose ◽  
Akihiko Yano ◽  
Kouichi Ohta ◽  
Katsuzo Segawa

2020 ◽  
Vol 28 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Katie A. Conway ◽  
Jason R. Franz

The authors elucidated functional limitations in older adult gait by increasing horizontal impeding forces and walking speed to their maximums compared with dynamometry and with data from their young counterparts. Specifically, the authors investigated which determinants of push-off intensity represent genuine functionally limiting impairments in older adult gait versus biomechanical changes that do not directly limit walking performance. They found that older adults walked at their preferred speed with hallmark deficits in push-off intensity. These subjects were fully capable of overcoming deficits in propulsive ground reaction force, trailing limb positive work, trailing leg and hip extension, and ankle power generation when the propulsive demands of walking were increased to maximum. Of the outcomes tested, age-related deficits in ankle moment emerged as the lone genuine functionally limiting impairment in older adults. Distinguishing genuine functional limitations from age-related differences masquerading as limitations represents a critical step toward the development and prescription of effective interventions.


BMJ Open ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. e027728 ◽  
Author(s):  
Siobhan Leahy ◽  
Marica Cassarino ◽  
Matthew DL O' Connell ◽  
Liam Glynn ◽  
Rose Galvin

IntroductionTwo major global health challenges are the rapidly ageing population and the high prevalence of obesity in all age groups. Older adults are also susceptible to age-related loss of muscle strength, termed dynapaenia. The co-occurrence of both obesity and dynapaenia, termed dynapaenic obesity (DO), has been associated with poorer health outcomes and increased healthcare usage compared with either state alone. The purpose of this systematic review is to quantify the prevalence and incidence of DO in older adult populations, and to explore the association between DO and health outcomes, specifically chronic disease and multimorbidity, functional disability and healthcare usage.Methods and analysisUsing the Meta-analyses Of Observational Studies in Epidemiology guidelines, we will conduct a systematic review of cross-sectional and longitudinal observational studies of older adults, which include measures of DO and specified outcomes. Detailed literature searches of will be conducted using six electronic databases: Excerpta Medica dataBASE (EMBASE), PubMed, MEDLINE, SCOPUS, ScienceDirect and Cumulative Index of Nursing and Allied Health Complete (CINAHL), including articles published from database inception until Febuary 2019. The reference lists of included articles will also be searched. Two independent reviewers will undertake a three-step screening and review process using the Population, Risk Factor, Outcome framework to define eligibility. The Newcastle Ottawa Scale for non-randomised studies will be used to assess risk of bias and to rate study quality. The findings will be synthesised in a narrative summary, and a meta-analysis will be conducted where appropriate.Ethics and disseminationEthical approval is not required for this systematic review. Findings from this research will be submitted for peer-reviewed publication in academic journals, and presented at relevant academic conferences.PROSPERO registration numberCRD42018112471.


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