About

Zev Binder, M.D., Ph.D., is a Research Assistant Professor of Neurosurgery and the Scientific Director of the Adult Brain Tumor Tissue Bank at the University of Pennsylvania's Perelman School of Medicine. He has been working with Dr. O'Rourke since 2015. Dr. Binder's educational background includes a B.S. in Biochemistry from the University of California at Davis, an M.D. from Pennsylvania State University College of Medicine, and a Ph.D. in Chemical and Biomolecular Engineering from Johns Hopkins University. His research focuses on translational glioblastoma (GBM) research with an emphasis on immuno-oncology. He works on GBM model development, characterization, and incorporation into ongoing research efforts. His contributions include developing CAR T cell therapies for glioblastoma, exploring brain-wide neuronal circuit connectomes of human glioblastoma, and investigating metabolic and radiogenomic signatures in recurrent glioblastoma. Dr. Binder's work aims to advance understanding and treatment of CNS malignancies through innovative immunotherapeutic strategies and molecular research.

Research topics

• Medicine
• Oncology
• Artificial Intelligence
• Computer Science
• Internal medicine
• Cancer research
• Computational biology
• Chemistry
• Pharmacology
• Bioinformatics
• Surgery
• Biology
• Pathology

Selected publications

• Abstract A056: Growth rates of patient-derived tumor organoids reflect heterogeneity in tumor plasticity among glioblastoma patients

  Cancer Research · 2026-03-23

  article

  Abstract Glioblastoma exhibits extensive intra-tumoral heterogeneity and plasticity, which significantly compromise treatment outcomes. Patient-derived glioblastoma organoids (GBOs) are emerging as a novel preclinical model for glioblastoma. Here, we analyzed the extent to which these GBOs replicate patients’ tumour plasticity and clinical behaviors. We found that GBOs derived from 32 patients exhibit heterogeneous growth rates in culture, as determined by analysis of GBO phase-contrast microscopy images over time. Kaplan-Meier survival analysis showed that GBO growth rates correlated with patients' overall survival, with faster-growing GBOs originating from resected tumor samples of patients who presented shorter overall survival (n=31 patients with available survival data, p=0.006, HR=3.1). Bulk RNA-seq analysis of resected tumor tissues (n=6) that generated fast-growing GBOs revealed lower expression of cell-cycle genes compared to those that generated slow-growing GBOs. This characteristic, however, was reversed when analyzing GBO RNA-seq data (n=6), suggesting a higher capacity for adaptation (plasticity) in glioblastoma tumours in the fast group. Supporting this concept, results from a comparative analysis of tumours and matched GBOs using bulk RNA-seq (n=6) and scRNA-seq (n=7) revealed greater transcriptional changes from tumor to GBO in the fast group (number of differentially expressed genes (nDEG) fast group= 1,848; nDEG slow=706), characterized by an increased number of cells in neural precursor (NPC)-like and oligodendrocyte precursor (OPC)-like tumour cell states and a reduction of cells in mesenchymal-like (MES) tumour cell states. Analysis of differentially expressed genes between fast- and slow GBOs (and matched resected tumour tissues) identified nicotinamide N-methyltransferase 1 (NNMT1) as a key enzyme potentially driving increased plasticity of fast tumours. In contrast, slow-growing GBOs activate NF2L2-dependent gene expression and inflammatory cytokine production upon culture, suggesting a stress-response mechanism of adaptation. DEGs analysis further identified 12 and 5 genes as biomarkers for fast and slow glioblastoma groups. These results suggested that GBO growth rates reflect heterogeneity in patients' tumour plasticity, with highly plastic tumor better equipped to resist and adapt to therapeutic treatment and therefore leading to poor survival outcomes. We confirmed this hypothesis by analysing clinical trial RNA bulk-seq data from two independent studies and found that biomarkers associated with the fast group were highly enriched in trial arms with poor survival outcomes. In summary, our results further highlight new biomarkers and potential targets against glioblastoma tumours stratified by their plasticity capacity and prognostic outcomes. Citation Format: Guillermo Gomez, Kaitlin Scheer, Erica Yeo, Chloe Shard, Helen Palethorpe, Anahita Fouladzadeh, Nga Truong, Sakthi Lenin, Rebecca Orsmby, Niclas Skarne, Bryan Day, Minh-Son To, John Toubia, Parul Mittal, Clifford Young, Conor Ryan, Annika Mascarenhas, Vanesa Tomatis, Anna Brown, Melinda Tea, Manuela Klinger-Hoffmann, Peter Hoffmann, Yusha Sun, Fadi Jacob, Xin Wang, MacLean Nasrallah, Zev Binder, Donald O'Rourke, Guo-Li Ming, Hongjun Song, Bryan Day, Stuart Pitson, Michael Brown, Santosh Poonnoose, Tessa Gargett, Ashwini Patil, Lisa Ebert. Growth rates of patient-derived tumor organoids reflect heterogeneity in tumor plasticity among glioblastoma patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A056.

  PublisherDOI

• Generation of Allogeneic <scp>CAR</scp> ‐T Circumvents Functional Deficits in Patient‐Derived Autologous Product for Glioblastoma

  International Journal of Cancer · 2026-04-24

  articleOpen access

  Glioblastoma (GBM) is the most common malignant brain tumor in adults, with a poor prognosis despite aggressive standard of care. Chimeric antigen receptor T-cell (CAR-T) therapy has shown promising results in liquid malignancies, but clinical trials in GBM targeting various tumor antigens have not shown durable clinical benefit. While this may be attributable to various tumor-intrinsic immune evasion strategies characteristic of GBM, little work has been done to assess whether the issue is due to the quality of the CAR-T treatment itself. Currently, CAR-Ts for GBMs and liquid malignancies are manufactured in an autologous setting in which T-cells are extracted from patients, engineered ex vivo, and subsequently reinfused back. However, peripheral T-cells taken from untreated GBM patients have demonstrated qualitative and functional deficits, which may contribute to suboptimal treatment outcomes. Thus, we aimed to establish whether CAR-Ts generated from GBM patients would show reduced efficacy in comparison to healthy donors using our previously validated CD133 CAR-T. In this work, we show pre-treatment exhaustion and reduced survival advantage in autologous, patient-derived CD133-targeting CAR-T cell products using an orthotopic xenograft model of human GBM. To overcome the functional and logistical considerations of autologous therapy, we additionally aimed to generate an "off-the-shelf" allogeneic CD133 CAR-T. Using CRISPR gene editing technology, we generated TCR-knockout CAR-T cells with comparable pre-clinical efficacy to our autologous models. Ultimately, this work highlights the need to reassess autologous CAR-T therapy for GBM and consider allogeneic approaches as biologically informed therapeutic alternatives.

  PublisherDOI

• Abstract A018: Sitagliptin potentiates glioblastoma tumor cell killing by EGFRvIII-targeting CAR T cells

  Cancer Research · 2026-03-23

  articleSenior author

  Abstract Glioblastoma (GBM) is a grade IV glioma with a high incidence rate and limited survival outcome. Historically, chimeric antigen receptor (CAR) T cell therapy has been shown to be an effective treatment for hematological malignancies. However, in solid tumors, such as glioblastoma, CAR T cell therapy has been less successful due to the heterogeneous composition of GBM and the immunosuppressive tumor microenvironment. One approach to address T cell exhaustion and lack of persistence is to use adjuvant enhancers that may be able to increase CAR T cell efficiency. Sitagliptin is a drug that has primarily been used as a treatment for type II diabetes; however, it may also be effective in targeting glioma cells through enhancing T cell activity via dipeptidyl peptidase 4 (DPP4) inhibition. DPP4 can limit dendritic cell (DC) activity by breaking down chemokines and cytokines, while sitagliptin offers the potential to prevent these molecules from being degraded. This could increase DC activity and allow for greater activation of T cells. As combination therapies have been shown to be effective at addressing the heterogeneity of GBM, this study utilized CAR T cells with the addition of the sitagliptin drug. U87MG cells were engineered to express the EGFR variant III (EGFRvIII) protein, green fluorescent protein, and click beetle green luciferase protein. An EGFRvIII-targeting CAR, 2173 41BBz CAR, was lentivirally transduced in T cells obtained from a healthy donor. Impedance cytotoxicity assays were carried out on the Axion Biosystems ZHT analyzer using U87vIII target cells, 2173 41BBz CAR T cells, and three varying doses of sitagliptin: 50uM, 100uM, and 200uM. Combination treatment across all doses produced a synergistic effect against U87vIII tumor cell killing, with the greatest cytotoxicity observed for the 200uM dose of sitagliptin. At 24 hours post CAR T cell addition, target cells treated with sitagliptin at a dose of 200uM showed a ∼92% cytolysis with a p-value of 0.0010. Future research will focus on the mechanism of sitagliptin’s actions, starting by evaluating cytokine levels as an indication of enhanced T cell activity. Collectively, these findings suggest that sitagliptin may improve cytotoxicity against a larger portion of the heterogeneous glioblastoma tumor, potentially through increased activation of T cells. Citation Format: Laura O'Sullivan, Payal Grover, Sydney Dumont, Oriana Teran Pumar, Defne Bayik, Donald M. O'Rourke, Zev A. Binder. Sitagliptin potentiates glioblastoma tumor cell killing by EGFRvIII-targeting CAR T cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A018.

  PublisherDOI

• Abstract A024: CAR T cells locally delivered in porcine decellularized matrix hydrogels enhance survival in post-resection glioblastoma

  Cancer Research · 2026-03-23

  article

  Abstract Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, with a median overall survival of 12-15 months, despite maximal surgical resection, radiation, and temozolomide. While chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable efficacy against hematologic malignancies, its activity in GBM has been limited by the immunosuppressive tumor microenvironment (TME), adaptive resistance from the tumor, poor trafficking of CAR T cells after peripheral administration, limited diffusion across the blood-brain- and blood-tumor-barriers, and lack of CAR T cell persistence. Because GBM recurrence is predominantly local, we hypothesize that regional delivery of CAR T cells directly into the post-resection cavity can overcome the immunosuppressive TME and improve the duration and magnitude of antitumor activity. To test this, we developed a biomaterials-based approach to encapsulate CAR T cells within a decellularized porcine brain extracellular matrix (dECM) hydrogel that transforms from a viscous pre-gel solution into a self-supporting scaffold at physiologic temperatures. dECM hydrogels were characterized for DNA and protein content, gelation kinetics, macrostructure and pore size, and CAR T cell viability and release kinetics. Encapsulated and released CAR T cells retained full cytotoxic function in vitro, demonstrating tumor-killing activity equivalent to freshly manufactured CAR T cells within impedance assays. We developed an orthotopic NSG mouse model of recurrent U87MG-EGFRvIII+ GBM, in which resection surgery alone does not improve survival compared to untreated mice, in order to evaluate the therapeutic impact of local delivery of CAR T cells during the post-resection window. The local implantation of on-target EGFRvIII-CAR T cells within dECM hydrogels, after resection, produced durable tumor control and significantly prolonged survival when compared to resection alone or dECM loaded with off-target CAR T cells. Additionally, a single locoregional dose of CAR-loaded dECM significantly extended survival and suppressed tumor recurrence comparably to multiple doses administered intravenously. Notably, local delivery of CAR-loaded dECM gels achieved durable tumor control at one-tenth the systemic CAR T cell dose and conferred survival benefits comparable to repeated intravenous infusions of the same CAR T cell product. These studies demonstrate that biomaterials-guided local delivery of CAR T cells enables potent and durable immunotherapy for GBM, allowing for treatment at an early opportunity time window that overcomes key biological and delivery barriers plaguing systemic delivery of immunotherapies. Citation Format: Meghan Logun, Kelly Hicks, Lois Park, Logan Zhang, Zev Binder, Donald M. O'Rourke. CAR T cells locally delivered in porcine decellularized matrix hydrogels enhance survival in post-resection glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A024.

  PublisherDOI

• Pharmacologic DPP-4 inhibition promotes CD8⁺ T cell metabolic fitness to enhance anti-tumor activity

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-04-03

  articleOpen access

  Abstract Metabolic dysfunction is a hallmark of CD8 + T cell exhaustion in the tumor microenvironment. Thus, there is growing interest in developing strategies that enhance anti-tumor functions of CD8 + T cells via metabolic reprogramming. Here, we identify dipeptidyl peptidase 4 (DPP-4) as a previously unknown regulator of CD8 + T cell function and metabolism. We discovered that DPP-4 is upregulated in exhausted CD8 + T cells. Pharmacological inhibition of DPP-4 with the FDA-approved anti-diabetic drug sitagliptin transcriptionally and metabolically reprogrammed CD8 + T cells, increasing spare mitochondrial respiratory capacity, proliferation, cytotoxic mediator production, and antigen-specific cancer cell killing capability. The functional effects of sitagliptin were dependent on upregulation of glutamate decarboxylase 1 (GAD1), an enzyme that feeds glutamate into the tricarboxylic acid (TCA) cycle, highlighting a new role for GAD1 in CD8 + T cell respiration and proliferation. We found that systemic inhibition of DPP-4 in preclinical mouse glioblastoma (GBM) models prolongs survival in a CD8 + T cell-dependent manner, and retrospective clinical cohort analysis revealed better outcomes in GBM patients using DPP-4 inhibitors. Importantly, preconditioning of Chimeric Antigen Receptor (CAR) T-cells with DPP-4 inhibition enhanced their cytotoxicity, persistence, and therapeutic efficacy in pediatric GBM. Together, our findings provide mechanistic and biological rationale for repurposing readily accessible DPP-4 inhibitors to enhance anti-tumor CD8 + T cell responses.

  PublisherDOI

• Abstract A051: Early cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) dynamics following intracerebroventricular CAR T cell therapy predict response to treatment of recurrent glioblastoma (rGBM)

  Cancer Research · 2026-03-23

  article

  Abstract We previously demonstrated efficacy for bivalent chimeric antigen receptor (CAR) T cells targeting EGFR epitope 806 and IL13Ra2 (CART-EGFR-IL13Rα2 cells) in patients with rGBM. However, tumor assessment on magnetic resonance imaging (MRI) can be difficult following immunotherapy for brain tumors, and biomarkers to predict response to intracerebroventricular (ICV) CAR T cell therapy for GBM have not been developed. Given that TERTp mutations C228T and C250T are detected in the vast majority of GBM tumors and are not subject to spatial or temporal heterogeneity, we hypothesized that TERTp mutant copies in CSF ctDNA would increase rapidly as a result of tumor killing and be associated with response to treatment. METHODS: We adapted a previously published droplet digital PCR (ddPCR) assay for high-sensitivity detection of TERT promoter (TERTp) mutations C228T and C250T for longitudinal CSF samples obtained via Ommaya reservoir in patients treated in our phase 1 clinical trial of CART-EGFR-IL13ra2 cells. After cell-free DNA extraction, the TERTp locus was pre-amplified, and 7-deaza-dGTP (7dG) utilized to mitigate the deleterious effects of CpG-rich regions on mutation detection. Negative controls included CSF samples from patients with non-cancer neurologic conditions. Clinical tumor tissue next generation sequencing was used to identify the TERTp mutation. RESULTS: To assess sensitivity, we first applied the assay to CSF samples obtained intra-operatively from 15 GBM patients who received standard of care chemotherapy and radiation. The known TERTp mutations were detected in 13 patients (86.7%). TERTp mutations were undetectable in the CSF of 9 negative control patients with multiple sclerosis. Among 15 Day 0 (D0, pre-infusion) CSF samples obtained from patients with rGBM who received CART-EGFR-IL13Rα2 therapy, the known TERTp mutations were detected in 15 (100.0%). Among CART patients, D0 mutant copies/mL were correlated with MRI-determined D0 bidimensional tumor measurements (Spearman R=0.6879, P=0.0231). Patients with D0 mutant copies/mL below median had longer PFS (log-rank P=0.0380). Next, we analyzed 113 longitudinal CSF samples collected for 15 CART patients over the first month post-CART infusion. ctDNA levels peaked on D7 after infusion, with TERTp mutant copies/mL significantly higher than at D0 (P=0.0479). A D7 increase in mutant copies was negatively correlated with tumor size at D1 and at one month (Spearman R=-0.7000, P=0.0204 and Spearman R=-0.5714, P=0.1511, respectively). All patients with a durable response of &amp;gt;4 months had increased mutant copies within 7 days of CART infusion. For one patient with imaging showing significant tumor enlargement at 1 month followed by a decrease in tumor volume at the 2-month scan, D7 change in mutant copies/mL was +1407.5, the second highest increase of all patients, suggesting tumor killing and reinforcing MRI findings consistent with pseudoprogression. CONCLUSION: High-sensitivity ddPCR-based mutation detection in CSF may have clinical utility for prediction of response to ICV CART therapy. Citation Format: Sophia G. Giliberto, Rahul Chowdhury, Melinda R. Yin, Dominique G. Ballinger, Siri C. Dandu, Jacob E. Till, Adam S. Corner, Francisco A. Bizouarn, Donald M. O'Rourke, Zev A. Binder, Stephen J. Bagley, Erica L. Carpenter. Early cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) dynamics following intracerebroventricular CAR T cell therapy predict response to treatment of recurrent glioblastoma (rGBM) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A051.

  PublisherDOI

• Abstract LB138: Natural killer cell-based signaling in EGFR-targeted KIR-CAR T overcomes CD3-based CAR T functional deficits to eliminate resistant glioblastomas in vivo

  Cancer Research · 2026-04-17

  article

  Abstract Glioblastoma (GBM) is the most common primary brain cancer in adults, with a prognosis of 15-18 months’ survival despite standard treatment of resection, chemotherapy, and radiotherapy. Recent clinical trials investigating autologous chimeric antigen-receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) variants in GBM through single-chain variable fragments (scFv) recombined with 41BB-co-stimulation and CD3ζ activation showed encouraging radiographic evidence of early tumor reductions, within days of CAR T treatment. Unfortunately, this anti-tumor function was short-lived, with tumor outgrowth generally occurring within days to weeks, potentially attributed to rapid loss of T cell function due to exhaustion, or target antigen loss. In efforts to bypass CD3-based CAR signaling exhaustion and prolong CAR T anti-tumor function, the recombinant single-chain CD3ζ-based CAR was replaced with a more physiologic split-signal system derived from natural killer (NK) cells, utilizing killer immunoglobulin-like receptor (KIR) and DNAX-activation protein of 12 kDa (DAP12) activation to allow a more natural cellular activation/rest cycle upon target cell engagement and disengagement. Second-generation EGFR/EGFRvIII-targeted single-chain 41BB-CD3ζ CAR was replaced with multi-chain KIR/DAP12 CAR signaling, and CAR and KIR T cells were compared in vitro for recognition specificity, cytolytic function, cytokine secretion, and T cell differentiation phenotype. In vivo efficacy was evaluated in established CAR-resistant immunocompromised NOD/SCID/gamma-chain-/- (NSG) murine GBM xenograft models, where tumor size was evaluated by in vivo imaging and caliper measurements and survival per Kaplan–Meier graph. Following lentiviral transduction and ex vivo expansion, KIR-CAR T displayed an increased naïve-like phenotype, with reduced effector-memory cells compared with CD3-based CAR T. In vitro, both CAR and KIR-signaling formats conferred comparable target specificity, cytotoxicity, T cell activation and cytokine release. In contrast, in vivo KIR-CAR T cells repeatedly outperformed 41BB-CD3ζ CARs, with the most effective treatment delivered by an scFv targeting multiple EGFR tumor-associated variants, demonstrating superior tumor regressions, including complete anti-tumor responses and increased survival. With the same targeting specificity, similar cytokine production in vitro, and significantly increased anti-tumor functional impact and prolonged survival in vivo, EGFR-KIR-CAR has the potential for rapid translation to the clinic to overcome the limitations of CD3-based single-chain CAR T in treating patients with GBM. Funded by NIH grant DP2CA174502 (LAJ). Citation Format: Jun Xu, Radhika Thokala, Yibo Yin, Chong Xu, Alina C. Boesteanu, Alexandria P. Cogdill, Zev A. Binder, Logan Zhang, Jiasi Vicky Zhang, Enxiu Wang, Carl H. June, Donald M. O'Rourke, Michael C. Milone, Laura A. Johnson. Natural killer cell-based signaling in EGFR-targeted KIR-CAR T overcomes CD3-based CAR T functional deficits to eliminate resistant glioblastomas in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB138.

  PublisherDOI

• Abstract 3444: Spatial profiling of recurrent glioblastoma in a Phase I clinical trial reveals favorable immune remodeling induced by intracerebroventricular CAR T therapy

  Cancer Research · 2026-04-03

  article

  Abstract Recurrent glioblastoma (rGBM) is an aggressive brain tumor with median survival under one year after standard chemoradiation. Antigen heterogeneity, immune exclusion, and a suppressive tumor microenvironment (TME) limit responses to immunotherapy. A first-in-human phase 1 trial of intracerebroventricular EGFR/IL13Rα2 CAR T cells (CART-EGFR-IL13Rα2) in EGFR-amplified rGBM was feasible, produced manageable neurotoxicity, and induced radiographic tumor regressions in a subset of patients (NCT05168423).To understand how this therapy reshapes the local TME, we analyzed paired tumor resections from 6 patients enrolled in the phase 1 trial, with specimens obtained from the primary intracranial disease site at trial enrollment (pre-treatment) and at radiographic progression after CART-EGFR-IL13Rα2 infusion. Multimodal spatial profiling included regional transcriptomic and protein mapping (GeoMx), single-cell whole-transcriptome imaging (CosMx), and high-resolution spatial transcriptomics (Visium HD). We annotated tumor, myeloid, lymphoid, and stromal compartments and derived composite scores for stemness, invasion, cell death, and immune regulation. Neighborhood- and interaction-based analyses were used to compare cellular states and cell-cell communication.Across patients, post-treatment samples showed reduced expression of CAR target antigen and a shift in tumor-intrinsic programs toward less stem-like, less migratory, and more apoptotic states, despite radiographic progression. The post-treatment TME was remodeled, with fewer suppressive myeloid- and B-cell-rich niches and increases in interferon-responsive and T cell-associated activation programs. Spatial interaction analyses indicated that pre-treatment rGBM contained dense networks of myeloid-tumor and myeloid-T-cell contacts consistent with impaired antigen presentation and effector function. Post-treatment specimens, in contrast, showed partial disruption of these suppressive circuits and the emergence of microenvironments more permissive to T-cell infiltration and activity.In the parent phase 1 trial, CART-EGFR-IL13Rα2 was feasible &amp; induced radiographic tumor regressions in a subset of patients. This correlative spatial analysis suggests that prior EGFR/IL13Rα2 CAR T exposure can leave a less suppressive, more immunologically engaged TME at the primary site, even in resections obtained at radiographic progression. Together, these data support the idea that intracerebroventricular CAR T therapy may condition rGBM for subsequent immunotherapy. Myeloid and B-cell interactions are highlighted as candidate targets for armoring next-generation CAR T cells and for designing rational combination and sequencing strategies. Citation Format: Wesley V. Wilson, MacLean P. Nasrallah, Nakial Cross, Yael A. Day, Vanessa Gonzalez, Rachel M. Leskowitz, Amy Marshall, Julie K. Jadlowsky, Gabriela Plesa, Donald L. Siegel, Elizabeth O. Hexner, Joseph A. Fraietta, Carl H. June, Stephen J. Bagley, Donald O’Rourke, Zev Binder, Andrew J. Rech. Spatial profiling of recurrent glioblastoma in a Phase I clinical trial reveals favorable immune remodeling induced by intracerebroventricular CAR T therapy [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 3444.

  PublisherDOI

• Abstract 1338: DPP-4: A CD8+ T cell metabolic checkpoint and cancer immunotherapy target.

  Cancer Research · 2026-04-03

  article

  Abstract Exhaustion of CD8+ T cells in the tumor microenvironment is intertwined with metabolic dysfunction. Thus, metabolic reinvigoration of T cells is a promising cancer immunotherapy strategy. Here, we identify dipeptidyl peptidase 4 (DPP-4) as an immune checkpoint molecule driving the hypometabolic state of exhausted CD8+ T cells. We found that DPP-4 is highly expressed by CD8+ T cells infiltrating brain tumors, and its expression levels increase with terminal exhaustion. Pharmacological inhibition of DPP-4 with the FDA-approved sitagliptin, which is used for the management of type II diabetes, transcriptionally and metabolically reprogrammed CD8+ T cells to upregulate lymphocyte activation pathways and enhance mitochondrial spare respiratory capacity. Functionally, DPP-4 inhibition increased proliferation, antigen-specific cancer cell killing capability, and cytotoxic mediator production of mouse CD8+ T cells and IL13Ra2 CAR T cells in vitro. Mechanistically, inhibiting DPP-4 upregulated glutamate decarboxylase 1 (GAD1), an enzyme that feeds glutamate into the tricarboxylic acid (TCA) cycle. Pharmacological inhibition of GAD1 abrogated sitagliptin-mediated T cell proliferation and metabolic reprograming of mouse and human CD8+ T cells, underscoring a new role for this enzyme in T cell functional regulation. Systemic inhibition of DPP-4 prolonged survival in preclinical glioblastoma (GBM) models in a CD8+ T cell-dependent manner. Furthermore, retrospective analysis indicated that GBM patients on DPP-4 inhibitors, gliptins, have better outcomes compared to those receive standard of care alone or in combination with metformin. Collectively, our results support repurposing the clinically used and well-tolerated class of DPP-4 inhibitors to enhance cancer immunotherapy responses. Citation Format: Oriana Teran Pumar, Durga Prasad Gannamedi Hinder, Dylan Harwood, Julia Benedetti, Christine Ballard, Erika Ciervo, Clara Lopez Ruiz, Christine Rafie, Jonathan Mitchell, Brandon Emanuel Leon, Pedro Henrique Assenza Tavares Coroa, Bruno Colon, Michele Ceccarelli, Quinn T. Ostrom, Zev Binder, Dionysios Watson, Erietta Stelekati, Bjarne Winther Kristensen, David Lombard, Defne Bayik. DPP-4: A CD8+ T cell metabolic checkpoint and cancer immunotherapy target [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 1338.

  PublisherDOI

• Abstract A020: TGFβRII/Switch Receptor Armoring Redirects TGFβ Signaling to Enhance EGFR CAR T Therapy in Glioblastoma

  Cancer Research · 2026-03-23

  article

  Abstract Chimeric antigen receptor (CAR) T cell–based adaptive cell therapy represents a promising strategy for glioblastoma (GBM) treatment, yet clinical efficacy remains limited due to challenges such as an immunosuppressive tumor microenvironment (TME), high tumor heterogeneity, antigen escape, and restricted penetration across the blood–brain barrier. Transforming growth factor-beta (TGFβ), secreted by tumor cells, tumor-associated macrophages (TAMs), and other cells in many solid tumors, promotes an immunosuppressive TME and hinders immune responses, including suppression of T cell function and persistence as well as cytokine production. Here, we developed a new CAR construct by armoring CAR–epidermal growth factor receptor (EGFR) with TGFβRII ectodomain/Switch Receptor (CD40, OX40, or CD27). It is concomitantly designed to eradicate tumor cells via EGFR CAR targeting and converts the inhibitory signal of TGFβ in the TME into immune-activating tumor necrosis factor receptor superfamily (TNFRSF) costimulatory signals. This dual mechanism thereby promotes T-cell survival, proliferation, and effector/memory differentiation. These engineered CAR T cells exhibited enhanced functional activity, as evidenced by increased cytokine secretion and cytotoxicity against GBM tumor cells in a repeated stimulation assay. Mechanistically, TGFβRII pull-down/co-immunoprecipitation demonstrated recruitment of TRAF family adaptors in switch receptor CAR T cells, supporting downstream TNFRSF signaling. Treatment with TGFβRII/CD40 SR, OX40 SR, or CD27 SR in the patient-derived GBM 106 tumor sphere (PBT106-TS) orthotopic model demonstrated more effective tumor growth suppression compared with the EGFR-CAR T-treated group in mice. These results support a dual-function CAR-EGFR-TGFβRII/Switch Receptor platform that couples EGFR-targeted tumor recognition with TGFβ-responsive TNFRSF costimulatory signaling, providing a strategy to counteract TGFβ-driven immune suppression in GBM. Citation Format: Jungmin Park, Nannan Li, Jesse Rodriguez, Laura Zhang, Zev Binder, Donald O'Rourke. TGFβRII/Switch Receptor Armoring Redirects TGFβ Signaling to Enhance EGFR CAR T Therapy in Glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A020.

  PublisherDOI

Frequent coauthors

• Donald M. O’Rourke

  University of Pennsylvania

  126 shared

• Gary L. Gallia

  80 shared

• MacLean P. Nasrallah

  University of Pennsylvania

  65 shared

• Stephen Bagley

  University of Pennsylvania

  59 shared

• Vafi Salmasi

  Stanford University

  49 shared

• Steven Brem

  University of Pennsylvania

  49 shared

• Arati Desai

  University of Alabama at Birmingham

  45 shared

• Alessandro Olivi

  44 shared

Education

• PhD, Chemical and Biomolecular Engineering

  Johns Hopkins University

  2014

• MD

  Penn State College of Medicine

  2008

• BS, Biochemistry

  University of California Davis

  2004