Gregory L. Beatty
· MD, PhDVerifiedUniversity of Pennsylvania · Rehabilitation Medicine
Active 1994–2026
About
Gregory L. Beatty, MD, PhD, is a Professor of Medicine (Hematology-Oncology) at the University of Pennsylvania and an Attending Physician at the Hospital of the University of Pennsylvania. He serves as the Director of the Penn-Incyte Alliance, the Director of Translational Research at the University of Pennsylvania Pancreatic Cancer Research Center, and Physician Lead for Pancreas Clinical Research at the university. His clinical expertise focuses on early-phase clinical trials for gastrointestinal malignancies, including pancreatic, esophageal, and colon cancers. Dr. Beatty has led pioneering studies such as the first clinical trial of CD40 immunotherapy for pancreatic cancer, which activates immune pathways involving macrophages and T cells to promote tumor regression. He has also conducted first-in-human trials of novel therapies like indoleamine 2,3-dioxygenase inhibitors and adoptive T cell therapies for pancreatic cancer. His research integrates basic science and clinical investigations to explore the role of innate and adaptive immunity—particularly monocytes, macrophages, and T cells—in tumor biology within pancreatic and other gastrointestinal cancers. His laboratory employs preclinical cancer models and advanced multiplex immunohistochemistry to understand immune regulation of tumors and to develop next-generation immunotherapeutic strategies. His work emphasizes the signaling pathways that mediate interactions between immune cells and tumor cells, the contribution of various cell types within the tumor microenvironment, and strategies to harness immune cells for effective anti-tumor responses. Dr. Beatty's research aims to improve therapeutic efficacy through combinatorial immunotherapies and to understand how treatments like chemotherapy and radiation influence immune cell behavior within tumors.
Research topics
- Medicine
- Cancer research
- Internal medicine
- Oncology
- Immunology
Selected publications
Scientific Reports · 2026-01-31
articleOpen accessSenior authorPancreatic ductal adenocarcinoma (PDAC) is a challenging malignancy to treat, but emerging evidence suggests that specific subtypes may respond more favorably to certain therapies. BRCA-mutated PDAC represents a distinct subtype that is particularly sensitive to DNA-damaging therapies. The current standard of care for advanced BRCA-mutated PDAC involves induction platinum-based chemotherapy followed by maintenance therapy with a poly (ADP-ribose) polymerase inhibitor (PARPi). However, the randomized phase III POLO trial, upon which this standard is based, did not demonstrate an improved overall survival in patients who received olaparib compared to those who received placebo, highlighting the need for new therapeutic approaches. Additionally, there is a lack of robust models that recapitulate the tumor microenvironment of BRCA mutated PDAC, limiting the development of next-generation maintenance treatment options. In this study, we developed a syngeneic and immunocompetent mouse model of Brca2-mutated PDAC. The model demonstrated high sensitivity to cisplatin plus gemcitabine, but limited efficacy of PARPi monotherapy. Induction with platinum-based chemotherapy sensitized tumors to PARPi maintenance therapy and promoted an exhausted, T cell-inflamed tumor microenvironment. However, resistance emerged which was associated with CDX2 expression and tumor differentiation. The addition of anti-PD1 treatment to PARPi maintenance enhanced tumor regression and prolonged overall survival. These findings provide preclinical support for ongoing clinical trials investigating immunotherapy with PARPi as a maintenance strategy in homologous recombination-deficient PDAC.
Cancer Research · 2026-04-03
articleAbstract Personalized neoantigen cancer vaccines have been at the forefront of therapeutic vaccination. However, although these neoantigen vaccines do induce neoantigen-specific T cell responses, the clinical effects are limited. Logistical challenges, such as the time required for developing personalized neoantigen vaccines, also limit their clinical utility. We were recently intrigued by a case at Penn where one of our patients had a 7.6 cm melanoma tumor and experienced a complete response after receiving the COVID-19 vaccine alone, consistent with a recent report that cancer patients who received the SARS-CoV-2 vaccination had improved survival. Further studies identified abundant SARS-CoV-specific T cells present in both the draining lymph node (LN) and in the necrotic tumor bed. At the same time, our preliminary experiment in mice showed a similar phenomenon that the activation of tumor-irrelevant CAR T cells by vaccination reinvigorated the host’s tumor-specific immunity and regressed established solid tumors. Specifically, when we used our recently developed lipid polymer vaccine (Ma et al, Science, 2019; Cell, 2023; Grzywa et al, Nat BME, 2025) carrying a chemical ligand Fluorescein (FITC) to specifically stimulate adoptively transferred bystander FITC-targeting chimeric antigen receptor (CAR) T cells in vivo in the lymph node as a negative control, yet unexpectedly we observed distal tumor regression to a level that’s comparable to vaccine stimulation of tumor-specific CAR T in syngeneic mouse models of pancreatic cancer and melanoma. In both settings, tumor volume was reduced by>70% within the first 72 hours, and this effect persisted for up to 2 weeks (with some cures of the melanoma). This marked antigen-independent tumor control is completely lost in Rag1-knockout (no endogenous T cells) and BatF3-knockout (deficient in antigen cross-presentation) recipient mice. FITC vaccine boosting of bystander FITC-CAR T induced a rapid and transient cytokine and chemokine release that distally remodels the tumor microenvironment. Notably, IFNg blockade completely abolished this tumor control. In the pancreatic cancer model, IFNg significantly upregulated PD-L1 expression in cancer cells. As a result, co-administration of anti-PD-L1 markedly extended long-term tumor control and animal survival. Collectively, these unexpected findings in both the melanoma patient and syngeneic mouse models of solid tumors suggested a previously unappreciated anti-tumor bystander effect associated with vaccine-mediated T cell activation. Citation Format: Leyuan Ma, Tomasz Grzywa, Ryan Tannir, Gregory L. Beatty, Alexander Huang. Vaccine stimulation of bystander t cells in the lymph node unexpectedly promotes tumor-specific host immunity to regress solid tumors [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 1350.
TLR2 signaling regulates T cell exclusion in pancreatic ductal adenocarcinoma.
JCI Insight · 2026-03-31
articleOpen accessSenior authorPancreatic ductal adenocarcinoma (PDAC) shows profound resistance to immunotherapy due to its immunosuppressive tumor microenvironment. Here, we studied the relationship between T cell infiltration and innate immune signaling in PDAC, identifying TLR2 as a key regulator of T cell exclusion. TLR2 expression correlated with T cell infiltration in both human and mouse PDAC tumors. Using genetic KO models and adoptive T cell transfer experiments, we found that TLR2 expression in both T cells and non-T cells contributes to T cell exclusion in PDAC. Notably, successful infiltration of adoptively transferred tumor-specific T cells required TLR2 deletion in both the transferred cells and the recipient host. The therapeutic implications of these findings are demonstrated through both genetic deletion and pharmacological inhibition of TLR2 using AAV-mediated and antibody-based approaches in murine models, resulting in decreased tumor growth and extended survival. Collectively, these findings identify TLR2 as a key modulator of T cell trafficking and immune suppression within the PDAC microenvironment, suggesting its potential as a therapeutic target for improving treatment outcomes.
2025-11-03
articleOpen accessSenior author<p>Patient characteristics for IF imaging of CD8, CK19, CTLA-4, LAG3, and PD-1</p>
2025-11-03
articleOpen accessSenior author<p>Efficacy of anti-PD1 and anti-CTLA4 is determined by the antibody clone</p>
Cell Reports Medicine · 2025-10-01 · 2 citations
articleOpen accessResponse determinants to immunotherapy in metastatic pancreatic ductal adenocarcinoma (mPDAC) remain unclear, limiting treatment advancements. We report a single-arm phase 1b/2 study (OPTIMIZE-1) evaluating the safety and efficacy of the cluster of differentiation 40 (CD40) agonist mitazalimab combined with modified FOLFIRINOX (mFOLFIRINOX), in chemotherapy-naive patients with mPDAC. Patients receive an initial dose of mitazalimab one week before starting biweekly cycles of mFOLFIRINOX plus mitazalimab. The study meets its pre-specified primary endpoint, achieving a confirmed objective response rate (ORR) of 42.1%. Median duration of response, progression-free survival, and overall survival was 12.6 months, 7.7 months, and 14.9 months, respectively. Multi-omic analyses of tumor and blood specimens identify a baseline tumor-intrinsic gene signature related to fibrosis associated with improved survival. Additionally, mitazalimab-induced increases in activated circulating myeloid, B cell, and T cell frequencies correlate with better outcomes. These results may inform future patient stratification strategies supporting a planned randomized confirmatory trial of mitazalimab with mFOLFIRINOX in mPDAC. This study was registered at ClinicalTrials.gov (NCT04888312). • Encouraging activity: ORR 42.1%, DoR 12.6 months, OS 14.9 months, and 18-month OS 36.2% • A baseline fibrosis gene-signature associates with OS • Mitazalimab induces intratumoral myeloid and T cell activation in objective responders • Mitazalimab-induced immune activation correlates with better outcomes Van Laethem et al. report that the combination of mFOLFIRINOX and mitazalimab has manageable safety and encouraging activity. Mitazalimab-induced immune activation and a fibrosis gene signature correlate with better outcomes. These results may inform future patient stratification strategies supporting a planned randomized confirmatory trial in mPDAC.
2025-11-03
articleOpen accessSenior author<p>Patient characteristics for IHC images</p>
2025-11-03
articleOpen accessSenior author<div>Abstract<p>Pancreatic ductal adenocarcinoma (PDA) is characterized by a myeloid-enriched microenvironment and has shown remarkable resistance to immune checkpoint blockade (e.g., anti–PD-1 and anti–CTLA-4). In this study, we sought to define the role of myeloid immunosuppression in immune resistance in PDA. We report that although depletion of CSF1R<sup>+</sup> myeloid cells in combination with anti–PD-1 and chemotherapy triggers T-cell infiltration into PDA, it also causes compensatory remodeling of the myeloid compartment with limited tumor control. Combination therapy against multiple myeloid targets, including CSF1R, CCR2/5, and CXCR2, was insufficient to overcome treatment resistance. High-dimensional single-cell analyses performed on T-cell infiltrates in human and mouse PDA revealed upregulation of multiple immune checkpoint molecules, including PD-1, LAG-3, and CTLA-4. Combinatorial blockade of PD-1, LAG-3, and CTLA-4 along with chemotherapy and anti-CSF1R was necessary to trigger activation of peripheral CD4<sup>+</sup> and CD8<sup>+</sup> T cells and led to deep, durable, and complete tumor responses, with each immune checkpoint blockade agent contributing to efficacy. Our findings indicate that a comprehensive approach targeting both negative regulatory signals controlling T-cell function and the myeloid compartment will be fundamental to unveiling the potential of immunotherapy in PDA.</p></div>
2025-11-03
articleOpen accessSenior author<p>Antibody tables for FCM, automated IHC and IF, and in vivo studies</p>
2025-11-03
articleOpen accessSenior author<p>T cell activation in the peripheral blood is improved when immune checkpoint blockade is combined with chemotherapy and CSF1R+ cell ablation</p>
Recent grants
Mechanisms and therapeutic targets of cancer metastasis
NIH · $1.8M · 2019–2025
NIH · $812k · 2016
Targeting the liver for immunotherapy in pancreatic cancer
NIH · $3.7M · 2016–2026
Frequent coauthors
- 129 shared
Robert H. Vonderheide
- 66 shared
Jae W. Lee
Johns Hopkins University
- 61 shared
Drew A. Torigian
University of Pennsylvania
- 55 shared
Peter J. O’Dwyer
University of Pennsylvania
- 55 shared
E. Gabriela Chiorean
University of Washington
- 48 shared
Weijing Sun
University of Kansas Medical Center
- 48 shared
Babak Saboury
National Institutes of Health Clinical Center
- 48 shared
Kristen B. Long
Labs
Beatty LaboratoryPI
Education
- 2004
M.D.
University of Pennsylvania
- 2000
Ph.D.
University of Pennsylvania
- 1995
B.S.
Bucknell University
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