Abstract Purpose: We conducted a phase I trial to evaluate radiotherapy (RT) and nivolumab with the further addition of an indoleamine 2,3-dioxygenase 1 (IDO1) enzyme inhibitor (BMS-986205) in newly diagnosed patients with glioblastoma (GBM) IDH wild-type. Patients and Methods: In the current study, there were two primary cohorts of individuals. Cohort A included patients with O6-methylguanine-DNA methyltransferase (MGMT)–unmethylated GBM who received RT with concurrent and adjuvant nivolumab with escalating BMS-986205 doses. Cohort B included patients with MGMT-methylated GBM who received BMS-986205 at 25 mg daily with RT, nivolumab, and temozolomide (TMZ) followed by adjuvant TMZ. Patient outcomes were correlated with flow cytometric, transcriptome, general metabolite, and microbial metabolite analyses. Results: The treatments for both cohorts were moderately safe and tolerable. The treatment-emergent adverse events (TEAE) were mostly related to RT, TMZ, or the underlying disease and tumor progression. In cohort A, serious adverse events and TEAEs were predominantly lower grade, with no differences between the IDO1 enzyme inhibitor dosing cohorts. Dose-limiting toxicities reflected by increased transaminases (grade 3) were observed in two and three patients at the 50 and 100 mg levels of BMS-986205, respectively, with malaise observed in the 50 mg arm only. The 50 mg daily schedule was established as the recommended phase II dose (RP2D) in combination with RT and nivolumab. A number of exploratory correlative studies were also conducted. Conclusions: This single-arm, small phase I trial establishes a safety profile and RP2D for RT in combination with nivolumab and BMS-986205 for newly diagnosed patients with MGMT-unmethylated GBM (ClinicalTrials.gov: NCT04047706).

Abstract Background: Glioblastoma (GBM) is the most common aggressive primary brain tumor, with a median overall survival (OS) of ≈15-18 months despite standard of care (SOC). Aging is a major negative prognostic factor, with older adults showing worse OS. Senescent cells accumulate with age and contribute to poorer outcomes. Senolytics clear senescent cells and may improve responses in older hosts. While tumor-intrinsic molecular features appear age-independent, the aging brain microenvironment impact on GBM progression and immunity remains unclear. Objective: To define age-associated senescence patterns in tumor core and peritumoral (PT) brain in GBM patients and mouse models and assess whether senolytic enhance treatment responses in aged syngeneic and humanized GBM models. Methods: MRI-guided tumor core and PT biopsies from GBM patients (<65 vs. ≥65) underwent transcriptomic and single-cell analyses to assess age-related neuro-immune and senescence changes. Senescence across tumor regions was examined in young (7-9 weeks) and aged (97-104 weeks) C57BL/6 and INK-ATTAC mice with intracranial SB28 tumors (n=5/group). Flow cytometry quantified β-gal+ senescent populations among neurons, astrocytes, oligodendrocytes, microglia, and immune infiltrates from tumor core and extratumoral brain. Mice received brain radiation, anti-PD-1, and IDO enzyme inhibition, alone ± senolytics (dasatinib+quercetin) or AP compound-induced clearance p16INK4A+ senescent cells. A human GBM aging model was developed by depleting CD4+, CD8+, CD19+, and NK1.1+ cells in young and aged C57BL/6 mice, prior to patient-derived GBM43 (PDX) intracranial engraftment, followed by SOC radiotherapy + temozolomide ± senolytics. Results: Transcriptomic profiling showed minimal age-related changes in tumor core but marked alterations in older PT tissues. Aged PT microglia exhibited a senescent phenotype with an upregulation of senescence-associated secretory phenotype (SASP) genes. Senolytics or AP compound significantly reduced extratumoral β-gal+ microglia and synergized with radio-immunotherapy to extend OS in aged mice (p<0.05). In the humanized immunodepleted GBM43 PDX model, young and aged mice developed tumors, with faster mortality in older hosts. Therapeutic responses to SOC ± senolytics are ongoing. Conclusions: The PT brain is a key site of age-dependent immune dysfunction in GBM. Senescent microglia may create an immunosuppressive niche that limits the immunotherapy efficacy in older adults. Senolytics may restore treatment efficacy and improve outcomes in older GBM hosts. We developed a novel immunodepleted GBM PDX model to mechanistically evaluate the role of aging in human tumor progression and therapy resistance. Keywords: glioblastoma, peritumoral brain, aging, immunotherapy, senescence, microglia Citation Format: Manon Penco-Campillo, Olaya de Dios, Megan Callender, Kristen L. Lauing, Oluwatomilayo Odum, Taylor Koch, Lijie Zhai, Vikram C. Prabhu, Douglas E. Anderson, Anand V. Germanwala, Jigisha P. Thakkar, Prashant Bommi, Pilar Sanchez-Gomez, Frederick Varn, Derek Wainwright. Age-dependent neuro-immune changes in glioblastoma shape therapeutic response and reveal senescent microglia as a targetable vulnerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6826.

This study aimed to determine how age and IDO1 interact to affect the gut microbiome, microbial metabolite levels, and survival outcomes in subjects undergoing IDO1-targeted immunotherapy against glioblastoma (GBM). Serum and colon contents from younger 16-20- or older 92-118-week-old wild-type (WT), IDO1 knockout (IDO1-KO), and IDO1 enzyme null (IDO1-H350A) mice were analyzed for 16S rRNA gut microbiome composition and microbial-derived aromatic amino acid metabolites via LC/MS/MS. Fecal samples from younger 7-8 or older 81-85 week-old WT mice with intracranial syngeneic GL261 GBM cells treated with or without brain radiation (RT) and PD-1 mAb were also analyzed. Fecal and plasma samples from 12 newly diagnosed IDHwt/MGMT promoter unmethylated GBM patients who received RT plus PD-1 mAb and IDO enzyme inhibitor were also analyzed. Young and old IDO1-KO and IDO1-H350A mice demonstrated a unique gut microbiome signature with an elevated abundance of Bifidobacterium and Helicobacter (p<0.05) and a reduced abundance of Ventriosum and Sireaum compared to WT mice (p<0.001). Prevotellaceae, Muribaculum, Alistipes, Enterohabdus, Clostridia, and Akkermansia were different in IDO1-KO and IDO1-H350A mice compared to WT - but only in older mice. Serum microbiome-derived aryl-lactates phenyllactate (PLA), indolelactate (ILA), and 4-hydroxyphenyllactate (4HPLA) were increased in IDO1-KO mice compared to WT and IDO1-H350A mice (p<0.001) - but only in older mice. Older WT mice with GL261 GBM showed lower fecal aryl-lactates (PLA, 4HPLA, and ILA) compared to younger counterparts. Treatment with RT + PD-1 mAb also showed decreased serum indole propionic acid (IPA) levels in young but not old mice with GL261 GBM (p<0.05). Analyses from GBM patient baseline fecal samples revealed that higher abundance of Massilioclostridium coli, GGB3819-SGB5184, Dysosmobacter welbionis, and Phocaeicola plebeius was associated with longer survival (p<0.004), while higher levels of fecal ILA and lower levels of plasma IPA also correlated with elongated survival (p<0.04 and p<0.01 respectively). Combined treatment of RT + PD-1 mAb + IDO1 inhibitor decreased plasma IPA when compared to baseline (p<0.01). IDO1 possesses both enzyme- and non-enzyme-dependent effects that change gut microbiota composition and bioactive microbial aromatic amino acid metabolite levels, which is also influenced by aging. Certain gut microbiota species and metabolites may serve as prognostic markers for predicting outcomes to immunotherapy for GBM. These findings warrant further investigation into how IDO1 interacts with age to affect immunotherapeutic efficacy in subjects with GBM. Lijie Zhai, Akriti Shrestha, Kristen L. Lauing, Manon Penco-Campillo, Oluwatomilayo Odum, Prashant Bommi, Taylor Koch, Robert H. McCusker, Douglas E. Anderson, Anand Germanwala, Vikram C. Prabhu, Jigisha P. Thakkar, Jacob M. Allen, Rimas V. Lukas, Derek A. Wainwright. Age and indoleamine 2,3-dioxygenase 1 (IDO1) interact to affect gut microbiome homeostasis in subjects with glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2215.

Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive protein that inhibits antitumor immunity through both tryptophan metabolism and nonenzymatic functions. Drugs targeting IDO1 enzyme activity have failed to improve the overall survival of patients with cancer. Developing new therapeutics that neutralize both enzyme- and nonenzyme-derived immunosuppressive IDO1 effects is therefore of high interest. We previously described a novel proteolysis targeting chimera (PROTAC), NU223612, that degrades IDO1 in cultured human glioblastoma (GBM) cells, as well as in well-established brain tumors, in vivo. In this study, we rationally optimized the structure of our lead series to create NU227326, which degrades IDO1 with a DC50 of 5 nM in human GBM cells. Mechanistic studies showed that IDO1 degradation occurred through the ubiquitin-proteasome system and was sustained for at least 2 days, supporting NU227326 as a highly potent IDO1 PROTAC suitable for further studies in GBM and other human cancers.

Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median overall survival (OS) of 15-18 months. The median age of a GBM diagnosis is 68-70 years old, and, increased subject age at the time of diagnosis is inversely associated with GBM patient OS such that older adults have significantly worse survival outcomes compared to similarly treated younger counterparts. Senescent cells accumulate in the body during progressive aging and contribute to worse outcomes in older adult mice with GBM. Senolytics are pharmacological compounds that cause senescent cells to undergo cell death. To comprehensively profile the treatment effect of senolytics combined with or without radio-immuno-therapy in mice with GBM across the lifespan. Young 7-9- and older adult 97-104-week-old wild-type (WT; C57BL/6) and 110-130-week-old INK-ATTAC (C57BL/6) mice with or without intracranial SB28 cells were treated with or without brain radiotherapy, PD-1 mAb, and an IDO enzyme inhibitor with the senolytics, dasatinib + quercetin, or the AP compound that induces p16INK4A+ senescent cell death in INK-ATTAC mice. Flow cytometric quantification of cells that are positive for beta-galactosidase, a marker for senescent cells, by flow cytometry was performed on brain-resident neurons, astrocytes, oligodendrocytes, as well as microglia in the tumor and non-bulk tumor mass brain parenchyma and correlated with overall survival. Immunofluorescence analysis of CD8+/granzyme A+ lymphocytes, CD68+/CD206+ macrophages, as well as endomucin+ endothelial cells was conducted across treatments and age groups. The treatment with senolytics or AP compound decreases beta-galactosidase+ microglia in the older adult brain with GBM (p<0.05). Older adult mice with a brain tumor show a significant decrease of endomucin staining as compared to younger counterparts (p<0.05). Strikingly, treatment with senolytics reversed this effect in older adults. Combining radio-immuno-therapy with senolytics improved overall survival of older adult mice with intracranial GBM (p<0.05). Our ongoing work aims to understand how senescent microglia affect neuronal health and function in older adults with GBM, as well as how senolytic treatment-induced vascular remodeling is associated with enhanced immunotherapeutic efficacy. Manon Penco-Campillo, Lijie Zhai, Prashant Bommi, Patience Oluwatomilayo Odum, Kristen L. Lauing, Robert Ladd, Olaya de Dios, Irene Gómez-Soria, M Angeles Ramírez-González, Douglas E. Anderson, Anand V. Anand Germanwala, Vikram C. Prabhu, Jigisha P. Thakkar, Pilar Sanchez-Gomez, Derek A. Wainwright. Senolytics decrease senescent microglia, remodel the vasculature, and improve survival in older adults with glioblastoma during co-treatment with immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6434.

This phase I trial evaluated the IDO1 enzyme inhibitor, BMS-986205, with radiation (RT) and nivolumab treatment in newly diagnosed patients with GBM IDHwt. Cohort A received RT + nivolumab with escalating BMS-986205 doses in MGMT unmethylated GBM patients. Cohort B received the highest dose of BMS-986205 with nivolumab and standard RT/temozolomide (TMZ) TMZ in MGMT methylated GBM patients. The treatments were found to be safe and tolerable. The median overall survival was 11.5 (95% CI: 3.71, 33.8) and 26.9 months (95% CI: 8.94-NR) while the 2-year survival rates were 33% (95% CI: 10.3%, 58.8%) and 60% (95% CI: 12.6%, 88.2%) for MGMT unmethylated and methylated GBM, respectively. Longer patient survival was associated with higher CD8+ T cell levels, higher microbial aryl-lactate levels, higher abundance of Massilioclostridium coli, Dysosmobacter welbionis, and Phocaeicola plebeius in the stool, a younger age, and a lack of gross total resection. (ClinicalTrials.gov: NCT04047706).

Abstract BACKGROUND Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a poor median survival rate. Despite the aggressive standard of care treatment combining surgical resection, chemo-, and radio-therapy, the median overall survival (OS) is only ~15-18 months. Progressively increasing subject age is inversely associated with GBM patient OS such that older adults tend to have significantly worse survival outcomes compared to younger counterparts. Senescent cells accumulate in the body during progressive aging and contribute to worse outcomes in older adult mice with GBM. Senolytics are pharmacologics that cause senescent cells to undergo cell death. OBJECTIVE To comprehensively profile the treatment effect of senolytics combined with or without immunotherapy in mice with GBM across the lifespan. METHODS Young 7-9- and older adult 97-104-week-old wild-type (WT; C57BL/6) and 110-130-week-old INK-ATTAC mice with or without intracranial SB28 cells were treated with or without brain radiation (RT), PD-1 mAb, and an IDO enzyme inhibitor with the senolytics, dasatinib + quercetin, or the AP compound that induces p16INK4A+ senescent cell death in INK-ATTAC mice (n=5/group). The quantification of beta-galactosidase positive cells by flow cytometry was performed on brain-resident neurons, astrocytes, oligodendrocytes, microglia, as well as dendritic cells, macrophages, neutrophils, T cells in the tumor and non-tumor bulk mass. Overall survival was also evaluated. RESULTS Senolytics or AP compound treatment both decrease beta-galactosidase positive microglia in the older adult brain with GBM (p<0.05). Combining radio- and immuno-therapy with senolytics improves overall survival of older adult mice with intracranial GBM (p<0.05). CONCLUSIONS Our ongoing work aims to understand how senescent microglia affect neuronal health and function in the older adult brain with GBM. KEYWORDS Glioma, senescence, senolytic.

Background: Increased age is a strong and unfavorable prognostic factor for patients with glioblastoma (GBM). However, the relationships between stratified patient age, comorbidities, and medications have yet to be explored in GBM patient survival analyses. Objective: To evaluate co-morbid conditions, tumor-related symptoms, medication prescriptions, and subject age for patients with GBM and to establish potential targets for prospective studies. Methods: Electronic health records for 565 patients with IDHwt GBM were evaluated at a single center between January 1, 2000 and August 9, 2021 were retrospectively assessed. Data were stratified by MGMT promoter methylation status when available and were used to construct multivariable time-dependent cox models and intra-cohort hazards. Results: Younger (<65 years of age) but not older (>= 65 years) GBM patients demonstrated a worse prognosis with movement related disabilities (P < 0.0001), gait/balance difficulty (P = 0.04) and weakness (P = 0.007), as well as psychiatric conditions, mental health disorders (P = 0.002) and anxiety (P = 0.001). In contrast, older but not younger GBM patients demonstrated a worse prognosis with epilepsy (P = 0.039). Both groups had worse survival with confusion/altered mental status (P = 0.023 vs < 0.000) and an improved survival with a Temozolomide prescription. Older but not younger GBM patients experienced an improved hazard with a prescription of ace-inhibitor medications (P = 0.048). Conclusion: Age-dependent novel associations between clinical symptoms and medications prescribed for comorbid conditions were demonstrated in patients with GBM. The results of the current work support future mechanistic studies that investigate the negative relationship(s) between increased age, comorbidities, and drug therapies for differential clinical decision-making across the lifespan of patients with GBM.

Abstract OBJECTIVE This study aimed to determine how IDO and subject age impact the gut microbiome and microbial metabolites during immunotherapy for glioblastoma (GBM). METHODS Serum and colon contents were collected from young 16-20- or older adult 92-118-week-old wild-type (WT; C57BL/6), IDO knockout (IDOKO), and IDO enzyme null (H350A) mice analyzed for 16S rRNA gut microbiome composition and microbial-derived aromatic amino acid metabolites via LC/MS/MS. Fecal samples from young 7-8 or older adult 81-85 week-old WT mice with intracranial GL261 brain tumors treated with or without brain radiation (RT) and PD-1 mAb were also analyzed. RESULTS Young and old IDOKO and H350A mice demonstrated a unique gut microbiome signature with an elevated abundance of Bifidobacterium and Helicobacter (p<0.05) and a reduced abundance of Ventriosum and Sireaum compared to WT mice (p<0.001). Prevotellaceae, Muribaculum, Alistipes, Enterohabdus, Clostridia, and Akkermansia were different in IDOKO and H350A mice compared to WT - but only in old mice. Serum aryl-lactates including phenyllactate, indolelacatate, and 4-hydroxyphenyllactate were increased in IDOKO mice compared to WT and H350A mice (p<0.001) – again, only in old mice. Older adult WT mice with GL261 showed lower fecal aryl-lactates compared to younger counterparts. Treatment with RT + PD-1 mAb decreased phenyllactate levels in old but not young mice with GL261 (p<0.05). CONCLUSIONS There are IDO enzyme- and non-enzyme-dependent effects on gut microbiota composition and bioactive microbial aromatic amino acid metabolites. These data warrant further investigation into how microbial metabolism affects immunotherapy efficacy and brain tumor survival across the lifespan.

PDF file - 13093K, Supplementary Fig.1: Loss of DDB2 expression in human colon cancer. Supplementary Fig.2: Low magnification IHC data showing reduced expression of DDB2 in high grade colon cancer samples. Supplementary Fig.3: Depletion of DDB2 increases invasivness of colon cancer cells. Supplementary Fig.4: Polyclonal DDB2 knockdown colon cancer cells exhibit increased tumorigenicity Supplementary Fig.5: Polyclonal DDB2 knockdown colon cancer cells exhibit EMT Supplementary Fig.6: DDB2 knockdown colon cancer cells generate aggressive tumors in nude mice Supplementary Fig.7: Low magnification picture showing EMT in xenografted tumors Supplementary Fig.8: DDB2 expression blocks EMT induced by hypoxia and TGF-beta Supplementary Fig.9: Chromatin-IP using T7-antibody demonstrating interaction of T7-DDB2 with the VEGF, Snail and Zeb1 promoters. Supplementary Fig.10: Transcription factor binding sites in the promoter fragments bound by DDB2 Supplementary Fig.11: Western blot analyses for the DDB2-associated proteins and XPC in DDB2-depleted cells. Supplementary Fig.12: Experimental metastasis assay with polyclonal DDB2 knockdown cells. Supplementary Fig.13: Expression of DDB2 does not inhibit proliferation in SW620 cells.

Abstract Checkmate 498 is a large, randomized, phase 3 clinical trial that demonstrated an improved hazard ratio for younger but not older adults with MGMT unmethylated GBM treated with RT + PD-1 mAb. In an effort to better understand the biological determinant, indoleamine 2,3 dioxygenase 1 (IDO1), and its relationship with reducing RT + PD-1 mAb treatment efficacy in older adults with GBM, we created and/or compared 20-26 month-old C57BL/6 background mice that were IDO1-T2A-GFP [wild-type (WT); negative control (n=16)], IDO1 enzyme null [with normal IDO1 expression potential but incapable of tryptophan metabolism (n=16)], IDO1KO (n=4), Ido1fl/fl (n=14), Lysm-Cre+→Ido1fl/fl [IDO1-deficient in monocytes, macrophages, and microglia (n=20)], CD11c-Cre+→Ido1fl/fl [IDO1-deficient in dendritic cells (n=23)], Tie2-Cre+→Ido1fl/fl [IDO1-deficient in endothelial cells (n=14)]. Mice were intracranially (ic.) engrafted with 5×103 syngeneic GL261 followed by treatment with radiation (RT) + PD-1 mAb beginning at 14-days post ic. IDO1 WT and IDO1 enzyme null mice had a survival rate of 12.5% and 18.75% at 90-day post ic., respectively, which was significantly reduced as compared to IDO1KO mice with a 75% survival rate (p< 0.05). Tie2-Cre+→Ido1fl/fl mice, CD11c-Cre+→Ido1fl/fl, and Lysm-Cre+→Ido1fl/fl mice had a 100%, 96%, and 70% survival rate at 90-day post ic., respectively, as compared to Ido1fl/fl mice with a 42% survival rate (p< 0.05). Significantly reduced kynurenine (KYN) levels were found in IDO1 enzyme null and IDO1KO mice as compared to WT mice (p< 0.001). Unexpectedly, kynurenine levels were also reduced in Tie2-Cre+→Ido1fl/fl but not in CD11c-Cre+→Ido1fl/fl, Lysm-Cre+→Ido1fl/fl or Ido1fl/fl mice (p< 0.05). Tryptophan (TRP) levels did not change between mouse groups. These data support the hypothesis that non-tumor cell IDO1 reduces immunotherapeutic efficacy in older adults with GBM through a TRP-KYN pathway-independent mechanism.

Supplementary Figures S1-S6

Abstract Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive rate-limiting enzyme that metabolizes the essential amino acid, tryptophan (Trp), into the downstream catabolite, kynurenine. IDO1 is expressed in >90% of patient-resected glioblastoma (GBM). We recently validated that IDO1 can suppress the anti-brain tumor immune response and ablate immunotherapeutic treatment efficacy through non-metabolic IDO1 activity. To-date, most IDO1-targeted therapy has focused on inhibiting tryptophan metabolism. This class of drugs has failed to improve the overall survival of patients with cancer. To overcome this failure, we developed a therapeutic agent that inhibits both IDO1 enzyme- and non-enzyme-activities in the form of an IDO1-Proteolysis Targeting Chimera (PROTAC). We previously published the characterization of a 1st generation lead compound (Bollu et al., 2022; J. Med. Chem) with a DC50 for IDO1 of 0.329 µM in human GBM cells. In a more recent investigation, we discovered a 2nd generation IDO1-PROTAC, NU227326, with 30× more potency and a DC50 of 10.4 nM in human GBM cells. IDO1-expressing U87, U138, and patient derived xenograft (PDX) GBM43 were treated with either IDO1-PROTAC, IDO1-mutant-PROTAC, IDO1 enzyme inhibitor, or IDO1 siRNA. Transcriptomic analysis revealed differentially expressed genes that were commonly regulated after treatment with the IDO1-PROTAC as compared to treatment with the IDO1-mutant-PROTAC or IDO1 enzyme inhibitor groups in U87, U138, and GBM43 cells. Mass spectrometry discovered 34 unique proteins that were differentially expressed inside of human GBM cells and an additional 20 unique proteins that were identified in the supernatant of cultured human GBM cells after IDO1-PROTAC treatment. Meta-analysis of the transcriptomic and proteomic analyses identified a novel factor that was unique to IDO1-PROTAC treatment. IDO1-PROTAC treatment-enriched GO terms were associated with nucleoside kinase and metallocarboxypeptidase activities. This study discovered multiple new pathways that immunosuppressive IDO1 non-metabolically regulates in human glioblastoma cells.

Supplementary Figures S1-S5

AbstractPurpose: Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan. Experimental Design: Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy. Results: Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice. Conclusions: This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM.

Supplementary Figures 1-6 from Bmi-1 Cooperates with H-Ras to Transform Human Mammary Epithelial Cells via Dysregulation of Multiple Growth-Regulatory Pathways