About

Gerald P Linette, MD, PhD, is a Professor of Medicine (Hematology-Oncology) at the Hospital of the University of Pennsylvania. His clinical expertise includes Medical Oncology, Melanoma and other advanced skin cancers, and Neuro-Oncology. His research focuses on Human Cancer Immunology, with a primary interest in developing systematic approaches to identify and validate cancer neoantigens. In collaboration with cancer genomics experts, he has created a bioinformatics pipeline to identify tumor-specific missense mutations that encode neoantigenic peptides, leading to the development of the first test of personalized cancer vaccination in humans with melanoma. His ongoing proof-of-concept trials aim to test neoantigens as targets for various immunotherapy strategies in melanoma and other solid tumors, with a focus on characterizing vaccine-elicited T cells using advanced molecular technologies. Additionally, he is involved in developing cellular therapies for cancer, exploring neoantigen-specific T cell therapy, and working collaboratively to find solutions to overcome obstacles created by the tumor microenvironment. His long-term goal is to advance and test personalized medicine-based approaches in cancer patients.

Research topics

• Internal medicine
• Oncology
• Medicine
• Pathology
• Surgery
• Immunology
• Pharmacology

Selected publications

• Abstract 5183: High-throughput <i>ex vivo</i> TCR-T cells screening identifies aggrephagy-driven, therapy-resistant clones in KRAS-mutant PDAC

  Cancer Research · 2026-04-03

  article

  Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by frequent KRAS-G12 oncogenic mutations, low immune cell infiltration, and early metastatic spread, leading to poor outcomes. Selective pressure from systemic therapies promotes the emergence of resistant clones and relapse. Patient-derived models that capture tumor heterogeneity are needed to optimize T cell receptor-engineered T cell (TCR-T) strategies and anticipate mechanisms of resistance. Methods: We developed a high-throughput ex vivo screening platform to test cell-based immunotherapies in patient-derived PDAC spheroids. KRAS-G12V-specific CD8+ TCR-T cells were co-cultured with KRAS-mutant 3D tumor spheroids under graded levels of cytotoxic pressure and monitored using automated image cytometry. Microcavity plates enabled parallel tracking of thousands of spheroids across two sequential TCR-T challenges. Surviving cells were profiled by single-cell RNA sequencing (scRNA-seq), followed by 2D regrowth assays and orthotopic transplantation into NSG mice to assess tumor-initiating capacity. Results: High-throughput resistance screening of over 33,000 microcavities revealed that 6.6% of 3D-PDAC spheroids remained viable after repeated TCR-T cell challenge, enriching for rare resistant subclones. After the first challenge, most cells exhibited an antiviral-like inflammatory response, characterized by increased levels of MX1, MX2, RIG-I, and interferon-stimulated gene expression. scRNA-seq after re-challenge revealed proliferating cells with upregulation of MHC II molecules and TUBA1B-associated aggrephagy pathways, implicating aggrephagy in immune escape. Resistant cells retained tumor-initiating potential and generated distant metastases in orthotopic NSG models (n = 10). In vitro, paclitaxel, a microtubule disassembly inhibitor, reduced colony formation by TCR-T-escaped clones, supporting a rationale for combination therapy. Conclusions: High-throughput ex vivo cytotoxicity screening of patient-derived PDAC models reveals aggrephagy-enriched, therapy-resistant clones and nominates rational combination partners such as paclitaxel. This platform may help anticipate patient-specific resistance to KRAS-targeted TCR-T therapy and guide the design of preventative combination strategies. Citation Format: Masoumeh Eshaghi, Fei Miao, Ali Abdollahzadeh, Sixing Chen, Jacopo Chiaro, Elahe Kamali G, Joshua Glover, Vineeth Koneru, Michael C. Milone, Miren L Baroja, Gerald P. Linette, Beatriz M. Carreno, Emma E. Furth, Vincenzo Cerullo, Joseph Fraietta, Carl H. June, Friederike Herbst-Nowrouzi. High-throughput ex vivo TCR-T cells screening identifies aggrephagy-driven, therapy-resistant clones in KRAS-mutant PDAC [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 5183.

  PublisherDOI

• Designing universal T cell therapies: strategies to evade natural killer cells

  Frontiers in Immunology · 2026-05-20

  articleOpen access

  Cell therapies such as chimeric antigen receptor (CAR) T cells and T cell receptor (TCR) T cells marked transformative advances in the treatment of hematologic and solid malignancies, respectively. Thus, adoptive T cell therapy (ACT), in which autologous T cells sourced from the patient constitute the starting immune population, represents a contemporary modality for the treatment of cancers. The need of an autologous cell product poses scientific and logistical challenges that need to be overcome to develop efficacious, scalable and cost-effective ACT. Peripheral blood lymphocytes procured from healthy donors can serve as a starting population for manufacturing a universal allogeneic T cell product offering solutions to both challenges. Recent advances in gene-engineering and -editing technologies have facilitated progress in the development and large-scale manufacturing of allogeneic T cell products. A strategy in development of allogenic ACT is ablation of the TCRαβ/CD3 complex to avoid graft versus host disease mediated by unrelated donor T cells. Mitigating host allogeneic T cells recognition is a complex endeavor that may begin with HLA-I/-II ablation, avoiding recognition and rejection of “non-self” HLA molecules. However, HLA-deficient T cells are susceptible to host NK cell recognition via the “missing-self” response. Here, we discuss immune evasive strategies taken to reduce NK cell mediated rejection of HLA-deficient T cells with particular emphasis on exploitation of HLA-E, a non-classical HLA-I, with regulatory function on NK cell activity. Current progress suggests that off-the-shelf universal T cell products may evolve to become a standard of care treatment options for certain disease indications.

  PublisherDOI

• Therapeutic scheduling of WEE1 inhibition preserves T cell function and promotes immune control of HPV⁺ tumors

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-12

  articleOpen access

  Abstract Human papillomavirus–associated oropharyngeal squamous cell carcinoma (HPV⁺ OPC) is driven by viral E6 and E7 oncoproteins, which disrupt G1 checkpoint control and impose selective dependency on WEE1-mediated G2/M regulation. While this vulnerability confers sensitivity to WEE1 inhibition, its immunologic consequences remain poorly defined, and the challenge of eliciting antitumor immunity without compromising immune fitness has limited clinical translation. Here, we show that WEE1 inhibition elicits durable antitumor immunity in immunocompetent models of HPV⁺ OPC. Using murine and human preclinical systems, we demonstrate that the WEE1 inhibitor azenosertib (ZN-c3) mediates tumor control through both cell-autonomous cytotoxicity and immune-dependent mechanisms requiring T cells and conventional dendritic cells. Mechanistically, HPV⁺ tumor cells are deficient in STING signaling and fail to mount canonical type I interferon responses. Instead, tumor cell–intrinsic cGAS drives immune activation through STING-competent host cells within the tumor microenvironment, revealing a non-cell-autonomous relay that circumvents viral immune evasion. Intermittent WEE1 inhibition preserves T cell fitness while maintaining antitumor efficacy, and mice achieving complete responses develop immunologic memory capable of rejecting tumor rechallenge. These findings establish intermittent WEE1 inhibition as an immune-permissive therapeutic strategy that enables antigen-specific T cell responses in HPV-driven malignancies and provides a mechanistic rationale for combination with immunotherapy.

  PublisherOA PDFDOI

• Tumor Associated Mitochondria Antigens (TAMAs) vaccine is effective on tumor and tumor associated endothelial cells: from the mechanisms to the clinical validation 3298

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description A major challenge for immunotherapy is the scarcity of effective cancer-specific antigens. Somatic mitochondrial (mt)DNA mutations can lead to Tumor Associate Mitochondria Antigens (TAMAs). Our group developed an effective antitumor dendritic cells based vaccine using mt lysates from renal cell carcinoma, harboring immunogenic mtDNA mutations, and we used it in combination with αPDL-1. The combination of therapies improves tumor control compared to single therapy and increases survival rate augmenting infiltration and reactivity of T cells. Interestingly, the combination of treatments favors tumor vessel normalization, which benefits tumor blood perfusion and decreases hypoxia enhancing reactive T cells infiltration, thereby boosting the efficacy of the TAMAs vaccine. Since we detected a correlation between CD8 cells infiltrating tumor and apoptosis of tumor vessel, we showed that endothelial cells that have naturally internalized tumor mitochondria, and hence TAMAs, are recognized by primed TAMAs T cells, which promote vessel pruning. To validate the translational relevance of the study, we demonstrated the immunogenicity of TAMAs in human healthy donors and the impact on tumor vasculature in patients harboring mt immunogenic mutations. In conclusion, we validate the immunogenicity of TAMAs in human and unveil a new immunological mechanism of tumor vasculature pruning opening a new strategy that could improve cancer therapies targeting both cancer and vasculature. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

  PublisherOA PDFDOI

• 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

• EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models

  Cancer Cell · 2025-02-20 · 47 citations

  article
  PublisherDOI

• Antigen-specific profiling identifies T-bet+ melanoma-specific CD8+ T cells associated with response to neoadjuvant PD-1 blockade

  Cancer Cell · 2025-12-31 · 3 citations

  article
  PublisherDOI

• Supplementary Tables and Figures from Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy

  2025-11-24

  articleOpen access

  &lt;p&gt;Supplemental tables: (1) Subject characteristics. (2) Cytogenetic profiles and high-risk features. (3) Prior treatment exposures and refractoriness. (4) CAR T cell product characteristics. (5) Products that did not meet target dose. (6) Adverse events of grade 3-4. (7) Cytokine release syndrome and ICANS. (8). Maintenance therapy. Supplemental Figures: (1) Study schematic and subject disposition, (2) Correlates of manufacturing success, (3) Hematopoietic recovery, (4) Post-infusion T cell phenotypes, (5) Correlates of in vivo expansion and manufacturing success, (6) Late post-infusion CAR T cell re-expansion, (7) Soluble BCMA, (8) Late-onset clinical responses, (9) MM cell BCMA expression, (10) Pre- and post-treatment Sox2-specific T cell responses in CART-BCMA monotherapy patients, (11) Pre- and post-treatment Sox2-specific T cell responses in CART-BCMA + huCART19 combination therapy patients, (12) Sustained post-treatment SOX2-specific T-cell responses.&lt;/p&gt;

  PublisherDOI

• Antigen-Specific Profiling Identifies T-bet-Expressing Melanoma-Specific CD8 T Cells Associated with Pathologic Response to Neoadjuvant Anti-PD-1

  SSRN Electronic Journal · 2025-01-01 · 1 citations

  preprintOpen access
  PublisherDOI

• Supplementary Figure 1 from Identification of Core Techniques That Enhance Genome Editing of Human T Cells Expressing Synthetic Antigen Receptors

  2024-09-03

  preprintOpen access

  &lt;p&gt;A, Representative ow cytometry plots of transduction efficiency of various synthetic receptors in control (unedited) and TRAC+TRBCKO T cells when editing is performed pre-stimulation. B, Stability of CRISPR editing over-time when performing post-stimulation editing.&lt;/p&gt;

  PublisherOA PDFDOI

Recent grants

• Integrated Discovery Pipeline for Tumor Neoantigens

  NIH · $2.7M · 2016–2022

• NIH Grant K23CA080851

  NIH · $398k · 2005

• Project 3 - Immune analysis of clinical trial samples

  NIH · $20.9M · 2018–2024

• PD-1 Blockade and Neoantigen-Specific T Cell Immunity

  NIH · $385k · 2016–2020

Frequent coauthors

• Patrick Y. Wen

  226 shared

• David A. Reardon

  Dana-Farber Cancer Institute

  175 shared

• J. Raizer

  Columbia University

  175 shared

• Jeffrey A. Sosman

  Northwestern University

  128 shared

• D. Schiff

  University of Pittsburgh

  125 shared

• Thomas Kaley

  Memorial Sloan Kettering Cancer Center

  125 shared

• Terri S. Armstrong

  Patient-Centered Outcomes Research Institute

  120 shared

• Lisa M. DeAngelis

  Memorial Sloan Kettering Cancer Center

  106 shared