About

Avery D Posey, PhD, is an Assistant Professor of Systems Pharmacology and Translational Therapeutics at the Perelman School of Medicine, University of Pennsylvania. He serves as the Director of Equal Opportunity Engagement at the Center for Cellular Immunotherapy. His educational background includes dual B.S. degrees in Bioinformatics and Computational Biology, and Biochemistry and Molecular Biology from the University of Maryland, Baltimore County, completed in 2005, and a PhD in Genetics from The University of Chicago, completed in 2011. His research focuses on cellular immunotherapy, with significant contributions to the development of engineered T cells for cancer treatment, including CAR T cell therapies, and their applications in cancer and autoimmunity. He has authored multiple publications on these topics, emphasizing advances in immunotherapy and the molecular targeting of cancers.

Research topics

• Cell biology
• Biology
• Immunology
• Internal medicine
• Cancer research
• Medicine

Selected publications

• Glycoengineering CAR-T cells to overcome galectin-3-mediated immunosuppression

  Frontiers in Immunology · 2026-02-18 · 1 citations

  articleOpen access

  Chimeric antigen receptor (CAR)-T cell therapy has transformed treatment for relapsed or refractory B-cell malignancies; however, limited in vivo persistence and treatment-limiting toxicities continue to constrain durable efficacy. Because T cell glycan signatures and related galectin-binding properties impact their effector function, we postulated that CAR-T cells similarly displayed signature glycan features that govern their vulnerability to immunosuppressive galectins. In this report, public data mining, galectin-binding and glycosyltransferase expression assessments and glycomics showed that galectin (Gal)-3 was elevated in lymphoma-associated microenvironments and that anti-CD19 CAR-T cells displayed abundant Gal-3-binding glycans, reduced expression of the Gal-3–inhibitory enzyme α2,6-sialyltransferase 1 ( ST6GAL1 ), and heightened susceptibility to Gal-3–mediated immunoregulation. To further explore this association, we enforced ST6GAL1 expression in anti-CD19 CAR-T cells and found that Gal-3-binding was obstructed and Gal-3-mediated cell death and IL-5-induction were reversed. Enforcing ST6GAL1 in CAR-T cells did not weaken tumoricidal activity and significantly improved anti-tumor responses and in vivo persistence. Collectively, this study identifies Gal-3 as a key extrinsic suppressor of CAR-T cell function and establish targeted cell surface α2,6 sialylation as a strategy to enhance CAR-T cell resistance to galectin-rich immunosuppressive microenvironments.

  PublisherOA PDFDOI

• Single-chain IL-23 secretion by CAR-T cells improves tumor control and persistence against solid tumors

  Molecular Therapy · 2026-01-10

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Harnessing the CD2 axis to broaden and enhance the efficacy of CAR T-cell therapies

  Blood · 2026-01-05 · 2 citations

  article

  ABSTRACT: Patients with T-cell lymphomas and leukemias have overall poor outcomes because of the lack of targeted and effective treatments, particularly in the relapsed and refractory settings. The development of chimeric antigen receptor (CAR) T cells against T-cell neoplasms is limited by a lack of discriminating T-cell antigens that allow for effective antitumor responses while preventing CAR T-cell fratricide. We hypothesized that targeting CD2, a pan-T-cell antigen, with anti-CD2 CAR T cells engineered to lack CD2 expression (CART2) would improve manufacturability and preclinical efficacy. Optimized CD2-knockout CART2 cells, generated using CRISPR-Cas9, eradicated primary patient-derived CD2+ hematological neoplasms in vitro and in vivo, secreted effector cytokines, and exhibited adequate proliferative capacity. Nevertheless, CD2 has a key costimulatory function, and its deletion could lead to CAR T-cell dysfunction. Therefore, we tested the role of the CD2:CD58 axis in CAR T cells, using the anti-CD19 CART models. We demonstrate that CD2 loss attenuates CART19 efficacy by reducing avidity for tumor antigen, costimulation, and ultimately in vivo activity. Analogously, we show that tumor CD58 loss reduces CART19 efficacy. To overcome this issue, we developed a novel programmed cell death protein 1 (PD-1):CD2 switch receptor that rescues intracellular CD2 signaling, particularly when programmed death-ligand 1 is engaged, thereby improving in vivo outcomes. Collectively, we studied the role of CD2 both as a target for CAR T-cell therapy and as a critical costimulatory protein, whose signaling can be rescued using the PD-1:CD2 switch receptor. This receptor can be incorporated into CAR T cells and provides an effective strategy to overcome CD2-signaling deficiencies.

  PublisherDOI

• Abstract 1529: ST6GAL1 enhanced CAR-T cells improve persistence and antitumor efficacy in DLBCL

  Cancer Research · 2026-04-03

  article

  Abstract Diffuse large B cell lymphoma (DLBCL) is the most common and aggressive B cell lymphoma, with poor outcomes for patients who relapse or are refractory to treatment. Chimeric antigen receptor (CAR)-T cell therapy offers a promising therapeutic option, yet limited persistence and functional impairment remain major barriers to durable responses. Galectin (Gal)-3, a carbohydrate-binding protein highly expressed in the DLBCL microenvironment, has been implicated in T cell dysfunction, but its role in CAR-T cell impairment has not been fully defined. We hypothesized that Gal-3 binds to CAR-T cell surface glycans, promoting apoptosis and loss of effector function. ELISA revealed significantly elevated Gal-3 levels in serum from DLBCL patients versus healthy controls (p<0.001). Flow cytometry confirmed strong Gal-3 binding to CAR-T cells, which correlated with increased apoptosis (p<0.01). To overcome this, we engineered CAR-T cells to overexpress the α2,6 sialyltransferase ST6GAL1 (ST6OE)CAR-T cells, which adds α2,6-sialic acids known to mask Gal-3-binding glycans. ST6OECAR T cells displayed markedly reduced Gal-3 binding, lower apoptosis (p<0.001), and improved viability and cytotoxicity in Gal-3high DLBCL co-cultures. Cytokine profiling further revealed that control CAR-T cells secreted elevated levels of interleukin-5 (IL-5),a Th2-associated cytokine linked to reduced antitumor activity. In contrast, ST6OE CAR-T cells exhibited significantly lower IL-5 production (p<0.01), indicating a shift toward amore cytotoxic, Th1-like functional profile. In a DLBCL xenograft model, ST6OE CAR-T treatment significantly reduced tumor burden and improved survival compared to control CAR-T cells (p<0.001). These findings demonstrate that ST6GAL1 overexpression mitigates apoptosis and IL-5-associated dysfunction, enhancing CAR-T cell persistence and antitumor efficacy. Glycoengineering CAR-T cells via ST6GAL1 provides a novel strategy to improve therapeutic outcomes for patients with DLBCL. Citation Format: Lee Seng Mari Lau, Maria Suarez, Brandon Fernandez, Aiza Berdalinova, Joseph Souchack, Aristotelis Antonopoulos, Anne Dell, Stuart Haslam, Avery D. Posey, Charles J. Dimitroff. ST6GAL1 enhanced CAR-T cells improve persistence and antitumor efficacy in DLBCL [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 1529.

  PublisherDOI

• CD2 costimulation bridges potent CAR-induced cytolysis and durable persistence

  Journal for ImmunoTherapy of Cancer · 2026-01-01 · 1 citations

  articleOpen accessSenior author

  BACKGROUND: Current second-generation CAR T cell products rely on CD28 or 4-1BB costimulatory domains, additions that respectively favor rapid cytolysis or long-term persistence, but rarely both. Preclinical modeling and retrospective analysis have linked CD2-CD58 engagement to superior preclinical and clinical responses, yet the direct contribution of CD2 intracellular signaling remains undefined. METHODS: flux and degranulation free of tonic viral signals; durable functional assays employed lentiviral CARs. Cytokine release, genome-wide transcriptional programs, and anti-tumor activity were assessed in vitro and in NSG xenograft models. RESULTS: flux signal intermediate to 28z and BBz CARs. Lentiviral CD2z CARs released a Th1-skewed cytokine panel and matched 28z cytolysis despite a lower acute cytokine release. Transcriptomic analysis characterized CD2z cells in an early effector-memory state: glycolytic, mTORC1, and TNFa-NF-κB hallmarks were upregulated, whereas exhaustion-up signatures were selectively depleted vs 28z. In vivo, a single CD2z infusion induced deep and durable tumor regressions over the 60-day observation period in subcutaneous mesothelin-positive mesothelioma and orthotopic TnMUC1-positive pancreatic tumor models, achieving tumor control comparable to 28z and more rapid early tumor clearance than BBz, while supporting peripheral T cell persistence similar to BBz. CONCLUSIONS: The CD2 cytoplasmic tail, in combination with CD3z, delivers balanced costimulation that couples brisk tumor debulking to T cell persistence. CD2z therefore may provide a simple, versatile alternative to canonical CD28 and 4-1BB modules for next-generation CAR T therapies.

  PublisherOA PDFDOI

• CD2 costimulation breaks the CD28 vs. 4-1BB tradeoff in CAR T cells

  Molecular Therapy Oncology · 2026-02-20

  articleOpen access1st authorCorresponding
  PublisherDOI

• LOXHD1 is an oncofusion-regulated antigen of ewing sarcoma

  Scientific Reports · 2025-04-15

  articleOpen access

  Ewing Sarcoma (EwS) is a rare pediatric malignancy characterized by a unique t(11:22) (q24;q12) translocation resulting in the pathognomonic EWSR1::FLI1 fusion. Recent reports indicate that the EWSR1::FLI1 oncofusion drives aberrant expression of numerous transcripts, including Lipoxygenase Homology Domains 1 (LOXHD1). Given its highly restricted protein expression pattern and role in EwS tumorigenesis and metastasis, LOXHD1 may serve as a novel immunotherapeutic target in this malignancy. LOXHD1 immunogenic epitopes restricted to HLA-A*02:01 allowed for the isolation of a high avidity αβTCR. LOXHD1-specific TCR engineered CD8+ T cells conferred cytotoxic activity against a panel of HLA-A*02:01+ EwS tumor cell lines and adoptive transfer led to tumor eradication in a mouse xenograft model of EwS. This study nominates LOXHD1 as an oncofusion regulated, non-mutated tumor associated antigen (TAA) with expression limited to inner hair cells of the cochlea, adult testis, and EwS.

  PublisherOA PDFDOI

• Abstract A104: The CA19-9 glycan is a viable target for CAR T cell therapy in PDAC

  Cancer Research · 2025-09-28

  article

  Abstract Chimeric antigen receptor (CAR) T cell therapy for pancreatic ductal adenocarcinoma (PDAC) has been challenging, in part due to the paucity of tumor-specific cell-surface targets. Here, we explored the feasibility and efficacy of CAR T cells directed against carbohydrate antigen 19-9 (CA19-9), a clinically useful tumor marker that is significantly elevated in most PDAC cases with limited expression in normal tissues. We designed and screened 14 CA19-9 CAR constructs harboring different single-chain variable fragments (scFvs) and intracellular signaling domains. Using both in vitro tumor coculture assays and in vivo cell- and organoid-derived xenograft models of human PDAC, we identified one design – AbLIFT15.28z – that enabled efficient and specific anti-tumor activity, including a high frequency of durable complete responses. Next, we engineered a murine version of AbLIFT15.28z and tested its efficacy in a syngeneic model that reflects the immunosuppressive milieu typical of most PDAC tumors. As mouse cells do not produce the CA19-9 antigen, we generated a CA19-9-expressing PDAC cell line by overexpressing enzymes essential for CA19-9 production. Subsequent in vivo testing confirmed the anti-tumor activity of murine AbLIFT15.28z CAR T cells in both primary and metastatic tumor settings, significantly reducing tumor burden and prolonging animal survival in an immunocompetent setting (median survival, unmodified T cell vs CAR T cell: orthotopic tumor model – 24 vs 47 days, n=8-12; lung metastatic tumor model – 44 days vs undefined (75% of mice survived for over 250 days), n=8 per group). These findings demonstrate the feasibility and potency of CAR T cells targeting CA19-9, providing a rationale for further clinical development. Citation Format: Feiyan Mo, Austin L. Good, Dannielle D. Engle, Avery D. Posey, Ben Z. Stanger. The CA19-9 glycan is a viable target for CAR T cell therapy in PDAC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr A104.

  PublisherDOI

• Constructing the cure: engineering the next wave of antibody and cellular immune therapies

  Journal for ImmunoTherapy of Cancer · 2025-08-01 · 1 citations

  reviewOpen accessSenior author

  Immuno-oncology has revolutionized cancer treatment by mobilizing the immune system to eliminate tumors. Although immune checkpoint inhibitors and T cell therapies have mediated durable responses in hematologic malignancies and select solid tumors, most patients still relapse or fail to respond. To overcome these limitations, novel, next-generation immune constructs, including bispecific-cell therapy combinations, armored cells, tethered cytokines, immune-stimulatory antibody conjugates, and in vivo gene editing, are being developed to enhance specificity, persistence, and immune activation. This Society for Immunotherapy of Cancer roadmap highlights emerging technologies that integrate, redirect, or potentiate immune response. We examine advances in construct design, strategies for clinical translation, and opportunities for combinatorial approaches. By addressing translational barriers and real-world challenges, we outline how innovative engineering can unlock a new era of safe, durable, and accessible immunotherapies. Realizing this potential will require coordinated efforts from researchers, clinicians, industry leaders, and policymakers to deliver curative outcomes to patients worldwide.

  PublisherOA PDFDOI

• Chimeric Antigen Receptor Regulatory T Cells Targeted Against Oxidized Low-Density Lipoprotein Reduce Atherosclerotic Plaque Development

  Circulation · 2025-11-21 · 6 citations

  articleSenior authorCorresponding

  BACKGROUND: Cardiovascular disease caused by atherosclerosis is responsible for 18 million deaths annually, highlighting a need for new medical therapies, especially for patients who are not eligible for percutaneous intervention. Atherosclerosis is driven by the accumulation of low-density lipoprotein and the formation of foam cells, accompanied by oxidative stress and the accumulation of oxidized low-density lipoprotein (OxLDL), a proinflammatory molecule. Lowering low-density lipoprotein levels is the mainstay of current treatment, along with blood pressure control and lifestyle changes, but to date, it has not been feasible to specifically target inflammatory pathways contributing to plaque development without considerable systemic side effects. Over the past decade, chimeric antigen receptor T cells have been used to treat cancer, resolve cardiac fibrosis, and restore immune balance in autoimmune diseases. In some instances, regulatory T cells endowed with chimeric antigen receptor (CAR Tregs) have been developed to treat autoimmunity through antigen-specific immunosuppression. METHODS: Using an inducible regulatory T cell platform, we created an anti-OxLDL-specific CAR Treg therapy and evaluated cell- and cytokine-mediated immunosuppression to reduce macrophage foam cell formation in vitro. We then tested murine anti-OxLDL CAR Tregs in immunocompetent mouse models of hyperlipidemia and atherosclerosis. RESULTS: Anti-OxLDL CAR Tregs reduced macrophage foam cell formation in vitro and significantly inhibited atherosclerotic plaque formation in vivo in immunocompetent mouse models. CONCLUSIONS: Anti-OxLDL CAR Tregs mitigate inflammation and plaque deposition associated with OxLDL and may offer a new therapeutic option for atherosclerosis.

  PublisherDOI

Recent grants

• Engineered T Cells Targeting Abnormal Glycans in Metastatic Prostate Cancer

  NIH · 2018–2022

Frequent coauthors

• Carl H. June

  Parker Institute for Cancer Immunotherapy

  108 shared

• Regina M. Young

  31 shared

• Sònia Guedan

  Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

  29 shared

• John Scholler

  University of Pennsylvania

  27 shared

• Denis Migliorini

  26 shared

• Shannon E. McGettigan

  Thomas Jefferson University

  25 shared

• Laurence J.N. Cooper

  18 shared

• Nicola J. Mason

  18 shared

Education

• PhD, Genetics

  University of Chicago

  2011

• BS, Bioinformatics and Computational Biology

  University of Maryland, Baltimore County

  2005

• BS, Biochemistry and Molecular Biology

  University of Maryland, Baltimore County

  2005