About

Saar I Gill, MBBS, PhD, is a Professor of Medicine (Hematology-Oncology) at the Hospital of the University of Pennsylvania. He is an attending physician at the Hospital of the University of Pennsylvania and a member of the Institute for Immunology and the Abramson Cancer Center. Dr. Gill serves as the Scientific Director of the University of Pennsylvania Cell Therapy and Transplant group and is the Director of the TCE in Gene-Edited Hematopoietic Stem Cell Transplantation. His educational background includes an MBBS in medicine and a PhD in immunology from the University of Melbourne. His clinical expertise encompasses blood and marrow transplantation, leukemia, myelodysplastic syndromes, myeloproliferative neoplasms, lymphoproliferative neoplasms, and bone marrow failure. His research focuses on tumor immunology, chimeric antigen receptor T cells, mouse models of human leukemia, murine xenografts, adoptive cellular therapy, genetic engineering of T cells, and flow cytometry.

Research topics

• Immunology
• Biology
• Medicine
• Genetics
• Internal medicine
• Oncology
• Cancer research
• Bioinformatics

Selected publications

• Predictive biomarkers of response to chimeric antigen receptor (CAR) T-cell therapy for pan-haematologic cancer

  Nature Biomedical Engineering · 2026-03-09 · 4 citations

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• The dawn of in vivo immune cell engineering in oncology

  Nature Biotechnology · 2026-01-22 · 1 citations

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• CD19 CAR T-Cell Therapy for Treatment of Chronic Graft-versus-Host Disease

  New England Journal of Medicine · 2026-04-29

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• Single-day nonactivated IL-18-armed CAR T cells establish a durable, stemlike state with enhanced persistence

  Blood · 2026-04-16

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  Chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment of B-cell malignancies, yet challenges including manufacturing delays, T-cell exhaustion, and limited persistence impede broader clinical success. Here, we report the single day production of non-activated CAR T-cells engineered to secrete interleukin-18 (IL-18), a pro-inflammatory cytokine that enhances T-cell function. These non-activated CART-IL18 cells exhibit robust anti-tumor efficacy across xenograft models of lymphoma, leukemia, and pancreatic cancer. IL-18 expression enhances the functional advantages of naïve-like non-activated CAR T-cells, resulting in improved persistence, metabolic fitness, and resistance to exhaustion. Single-cell transcriptomic analysis revealed upregulation of IL7R, KLF2, and MCL1, alongside suppression of inhibitory checkpoint genes such as PDCD1, TOX, and HAVCR2. Metabolomic profiling demonstrated enhanced mitochondrial bioenergetics, with increased spare respiratory capacity and accumulation of α-ketoglutarate, malate, and spermine. Functional in vitro and in vivo profiling demonstrated enhanced per-cell cytotoxicity and in vivo durability. We complemented these studies with single-cell transcriptomic and metabolomic analyses to define CAR T-cell biological states beyond what is captured by xenograft tumor clearance. This IL-18-enhanced, activation-free CAR T product offers a clinically actionable platform with the potential to reduce vein-to-vein time while improving product potency and persistence, providing a rationale for clinical testing in patients with tumors refractory to standard CAR T.

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• Survival after Chimeric Antigen Receptor T-cell Therapy Is Predicted By Fried’s Frailty Phenotype

  Transplantation and Cellular Therapy · 2026-02-01

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• Fried's frailty phenotype predicts survival in pts with relapsed/refractory lymphoma or myeloma undergoing chimeric antigen receptor T-cell therapy – a prospective, observational Study

  Blood · 2025-11-03

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  Abstract Chimeric antigen T-cell receptor (CART) therapy is highly effective for pts (pts) with relapsed/refractory (R/R) lymphoma/multiple myeloma (MM). However, due to concerns regarding tolerability, older pts are underrepresented in CART trials and real-world studies indicate that CART is underutilized in older adults. Methods to assess fitness for CART are ECOG, clinician gestalt and age. There is interest in improving risk stratification of older adults using objective measures. Fried's frailty phenotype (FP) uses subjective (exhaustion, reported weight loss, activity level) and objective (gait speed, grip strength) measures to categorize pts into fit, pre-frail, and frail. We have previously shown that FP predicts for overall survival (OS) in older stem cell transplant (SCT) recipients. We hypothesize that FP will be associated with progression-free survival (PFS) and OS in older pts with lymphoma/MM undergoing CART therapy. We prospectively enrolled pts ≥ 60 years planned for CART for R/R lymphoma/MM from May 2019 – 2023 on a clinical trial. We performed FP prior to CART infusion, and at 7 days (d), 14d, 21d, 1 month (mo), 3mo, 6mo and 12mo post-infusion. 36 pts were enrolled with a median age at CART infusion of 69 years (Range 60-81). 53% of pts had MM, of whom 63% had intermediate or high-risk disease by R-ISS. The remainder had lymphoma (diffuse large B-cell or follicular lymphoma) with IPI > 2 at diagnosis in 59%. Idecagtagene vicleucel and tisagenlecleucel were the most frequently administered CART products. Median follow up was 33mo. Median prior lines of therapy (LOT) was 3 (Range 1-7) and 47% had prior auto-SCT. Pre-infusion, majority had low ECOG scores (0-1, 81%), including 71% categorized as frail by FP. At pre-infusion FP, 35% of pts were fit (score 0), 44% were prefrail (score 1-2) and 21% were frail (score 3-5). Frail pts were more likely to be admitted for >7d for their CART infusion (OR 7.0, 95% CI 1.02-47.97, p=0.04). Frailty was not associated with risk of CRS, ICANS or 30-day hospital readmission. 13 pts had died by the time of analysis; all but 2 deaths were related to progressive disease. 2 non-disease related deaths were 1 death from COVID and 1 ICANS-related death from teclistamab after relapse 1 year and 2 years after infusion, respectively. At Day 21 post-infusion, 21% were fit, 57% were prefrail, and 21% were frail. At 1mo post-infusion, 25% were fit, 63% were prefrail, and 13% were frail. Being frail by FP at pre-infusion (p<0.001), Day 21 (p=0.03) or 1 month (p=0.009) post-infusion was associated with inferior OS from that time point. Median PFS in pre-infusion fit, prefrail, and frail pts were 23.4mo (95% CI 17.1-NR), 18.4mo (95% CI 6.8-13.8) and 4.0mo (95% CI 2.5-8.4), respectively. 2-year OS estimates were 100%, 93% and 14%, in fit, prefrail and frail pts respectively. 14 of 36 pts maintained or improved their FP from pre-infusion to 1mo; all but 3 received physical therapy (PT) while in hospital with 5 pts continuing PT outpatient. Notably, pts who maintained or improved their FP from pre-infusion to 1mo post-infusion had significantly better OS (p=0.05) than pts who had declines in their scores. Along with pre-infusion, day 21 and 1mo post-infusion FP scores, LDH (Mean 182 U/L) at the time of CART infusion was significantly associated with OS in the univariate Cox proportional hazards model (HR 5.22, 95% CI 1.43-19.18, p=0.013). Several factors including disease type, number of prior lines of therapy, use of bridging, stage at CART, IPI/RISS at diagnosis, HCT-CI, ECOG, presence of extra-nodal disease, CRS, ICANS, gender, age by decade, and BMI did not correlate with outcome. In pts ≥ 60 with R/R lymphoma/MM undergoing CART, 21% were frail by FP prior to CART. Frailty by FP pre-infusion, day 21 and 1mo post-infusion was associated with inferior OS as opposed to ECOG, HCT-CI, age or several disease related risk factors. FP may improve risk stratification in older adults undergoing CART. Pts with improvement in FP within 1mo post-infusion also had better outcomes. While better disease control could contribute to improved FP scores, most pts received PT to reverse frailty. Our future work aims to implement an exercise regimen to improve outcomes and to determine whether frailty is associated with adverse disease biology. Future work to uncover biologic mechanisms of frailty and adverse disease biology may identify novel targets for intervention to improve outcomes for frail pts.

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• Glucose transporter 5 enhances CAR-T cell metabolic function and serial killing

  Blood · 2025-11-03

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  Abstract Physiologic serum fructose levels range from 20-150. In the context of AML, fructose accumulates in the bone marrow, reaching concentrations of 2mM, 5mM and in some reports 8mM. Implicit in this observation is that fructose is produced by cells present in the bone marrow and diffuses into the larger blood volume of the periphery. Transmembrane flux of glucose and/or fructose is facilitated by glucose transporters (GLUT) that play a vital role in T cell metabolic reprogramming and anti-tumour function. GLUTs display preferential selectivity for carbohydrate macronutrients including glucose, galactose, and fructose. GLUT5, which selectively transports fructose over glucose, has never been explored as a genetic engineering strategy to enhance CAR-T cell serial killing and durable anti-tumor function in fructose-rich tumour environments. Here, we demonstrate that the expression of wild-type GLUT5 restores T cell metabolic fitness in glucose-free, high fructose conditions. We find that GLUT5 supports maximal glycolytic capacity, expedites ATP replenishments, and rescues IL-2 production by using fructose as the primary nutrient source. Using steady state tracer technology, we show that 13C6 fructose supports glycolytic reprogramming and TCA anaplerosis in CAR-T cells undergoing log phase expansion. In cytotoxicity assays, GLUT5 rescues T cell cytolytic function in glucose-free medium. The fructose/GLUT5 metabolic axis also supports maximal migratory velocity, which provides mechanistic insight into why GLUT5-expressing CAR-Ts have superior effector function as they undergo “hit-and-run” serial killing. Our findings have immediate translational relevance as GLUT5 confers a competitive edge in a fructose-enriched milieu, and is a novel approach to overcome glucose depletion in hostile tumour microenvironments (TMEs). Importantly, the source of fructose production has not been described. As sorbitol dehydrogenase (encoded by SORD) synthesizes fructose at the end of the polyol pathway, we profiled SORD abundance in human bone marrow using single cell transcriptomic data generated from the anti-CD123-CAR-T cell clinical trial (NCT04106076) performed at the University of Pennsylvania. UMAP visualization revealed SORD expression in AML blasts (CD33+ and CD34+). This was expected as they account for 20-80% of all the cells in the leukemic bone marrow. We found that the highest SORD transcript levels were mapped to a non-AML cell population. These cells are haematopoietic in origin (CD45/PTPRC+ cells). Interestingly, data from The Human Protein Atlas reveals that naive B cells express high levels of GLUT5 which could facilitate diffusion of fructose across the surface (Fig. S1B). scRNA seq data also indicated high Glut5 and GAPDH as well as LDHA in tumor cells which suggests that Glut5 is fueling glycolysis and the rapid growth of tumor cells These findings imply that Glut5 could be a target for cancer treatment. We recognize that AML blasts and CD123-CAR-T cells engineered to express GLUT5 may compete for fructose in the bone marrow. As GLUT8 also displays high affinity for fructose, it emerges as an important candidate to inspire similar approaches. Intuitively, select inhibitors of GLUT5 such as MSNBA (N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine; Ki of 3.2 ± 0.4 μM) can be combined with GLUT8-expressing CAR-T cells to bypass competition for fructose in AML. In a subset of patients Glut1 is high (SLC2A1) and these tumor cells do not express high levels of GAPDH or LDHA. These data suggest that the complete oxidation of glucose in the mitochondria maybe supporting the growth of AML blasts; positioning the complex 1 inhibitor metformin as an important candidate along with standard therapy. In summary, we show that T cell dependency on glucose can be mitigated by facilitating the metabolism of fructose, a closely related functional isomer of glucose. Our findings provide an important advance in the clinical applications of CAR-T cell therapy against AML, and potentially other tumors where fructose is abundant. Expressing glucose transporters to optimize fuel selection, expedite ATP replenishment, support cytokine production, and bolster anti-tumour function has been fraught with challenges. Here, we show that GLUT5 is an ideal candidate with immediate translational relevance, including CAR-Ts against AML.

  PublisherDOI

• Cytokine-medated expansion of clonal hematopoiesis after CART therapy

  Blood · 2025-11-03

  articleOpen accessSenior author

  Abstract Chimeric antigen receptor (CAR) T-cells are highly effective against relapsed and refractory B cell and plasma cell malignancies, but are associated with well-recognized acute toxicities such as cytokine release syndrome (CRS). Emerging long-term follow-up data has recently revealed that second primary malignancies (SPM) occur in CART recipients, with an incidence of 4.3% - 8.2%. Most SPM are myeloid malignancies such as myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML), representing approximately 50 - 60% of all SPM. These occur at a median of approximately 9 - 19 months after CART cell infusion. How CAR T cell therapy, which is not known to be genotoxic, influences subsequent myeloid neoplasms (SMNs) is unclear. One hypothesis suggests SMNs may arise from clones harboring mutations associated with clonal hematopoiesis (CH), whereby accumulation of somatic mutations in genes such as TET2 or DNMT3A can confer fitness advantages to individual hematopoietic stem and progenitor cells (HSPCs). Chronic exposure to inflammation can deplete healthy HSPCs, while HSPCs bearing CH mutations are thought to be protected. We postulated that severe acute inflammation, as can occur during CAR T-induced CRS, leads to selective expansion of CH HSPCs. To model the interaction of CAR T cell-mediated inflammatory factors and CH-associated mutations, we first modeled in vitro CRS by collecting supernatant from a co-culture of a CD19+ B-ALL cell line, CAR T cells targeting CD19, and autologous monocytes. This “CRS medium” contained markedly elevated concentrations of IL-1β, IL-2, IL-12p70, IL-23, TNF-α, and IFN-γ. Of these, TNFa and IFNy are frequently implicated as drivers of CH. Exposure to “CRS medium” for two weeks increased the variant allele frequency (VAF) of TET2KO ~ 2-fold and promoted the expansion of TET2KO HSPCs in culture by ~ 55-fold. VAF expansion in the presence of CRS cytokines was also observed in HSPC engineered to express IDH1 R132H and DNMT3A R749C (2x and 1.5x increases observed respectively). We then obtained bone marrow mononuclear cells (BMMC) harboring the CH-associated DNMT3AR882H mutation from a patient with MDS . These BMMC were incubated in serum obtained from patients who received CART19 for lymphoma before (“baseline serum”) or during (“CRS serum”) clinically-defined episodes of CRS. After 48 hours in patient serum, BMMC were plated in Methocult media for a 14 day colony assay. Cells exposed to CRS serum for 48 hours prior to plating exhibited ~2x increase in DNMT3A mutation frequency, while cells incubated with pre-CRS serum exhibited a slight decrease. Additionally, patient-derived TET2 mutant BMMC exhibited variable mutation dynamics, with two out of three samples showing mutation expansion after incubation in CRS serum. To understand the signals driving these increases in colony count and mutation frequency, we performed single cell RNA sequencing on DNMT3A mutant MDS BMMC exposed to baseline or CRS serum for 48 hours. This analysis revealed that CRS serum drives significant increases in transcription of cytokine response pathways, particularly type 1 interferon and TNF response pathways. These findings suggest that inflammatory cytokines produced by CAR T cells influence the survival and proliferation of CH mutation-bearing cells. Our results may provide an explanation for increasing reports of SMNs in patients receiving CAR T cell therapy, and highlight specific pathways that may drive this adverse outcome.

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• CAR-macrophage therapy for HER2-overexpressing advanced solid tumors: a phase 1 trial

  Nature Medicine · 2025-02-07 · 173 citations

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• Cytotoxic, natural killer-like ex-tissue resident memory T-cells circulate in human chronic graft-versus-host disease at diagnosis

  Blood · 2025-11-03

  articleOpen accessSenior author

  Abstract Emerging evidence implicates tissue resident memory T-cells (TRM) in chronic graft-versus host disease (cGVHD) immunopathology. While traditionally considered confined to tissues, recent studies indicate TRM can re-enter the circulation as “ex-TRM” in inflammatory conditions. However, the role of ex-TRM in cGVHD, and the link between peripheral blood (PB) and tissue-based immunopathology in cGVHD are not well understood. To identify and characterize ex-TRM in cGVHD, we utilized 10X Genomics 5' GEM-X technology to perform single-cell RNA sequencing (scRNA-Seq) and single-cell TCR sequencing (scTCR-Seq) on T-cell selected PBMC samples from patients with newly diagnosed, treatment-naive cGVHD (n=8) and post-allogeneic stem cell transplant (ASCT) matched controls (MC; n=5) who did not develop relapse or acute/chronic GVHD. Quality control (QC), normalization, clustering, principal component analysis, dimensionality reduction, and integration were performed with Seurat v5.2.1 in R v4.4.2. CD8+ effector memory (EM) subsets were re-clustered to enhance resolution for ex-TRM. TCR clonality was assessed in ScRepertoire, and antigen specificity was determined for alpha/beta TCR amino acid sequences using ImmuneWatch DETECT. Differences in continuous variables were assessed using the Wilcoxon rank-sum test, and Bonferroni correction was applied for differential gene expression (DGE) analysis. Significance was set at p < 0.05 All patients received matched donor transplants and tacrolimus and methotrexate for GVHD prophylaxis. There were no significant differences between cGVHD and MC for age, sex, donor type (related vs. unrelated), CMV serostatus, conditioning regimen, or sample timepoint post-ASCT. After QC, 29,107 CD8+ T-cells (17,938 cGVHD and 11,1169 MC) were analyzed. Re-clustering of CD8+ EM cells revealed a distinct cluster expressing canonical TRM markers (CXCR6, ITGA1, ITGAE, CD69) as well as TRM-associated genes CXCL13 and CRTAM, consistent with ex-TRM. To further validate the TRM-like signature, we performed cluster-based module scoring using: 1) the top 100 upregulated genes from our recent publication in TRM vs. non-TRM in explanted lung tissue from pulmonary cGVHD and 2) the top 200 upregulated genes from an external dataset comparing lung TRM to circulating EM T-cells in healthy controls. Module scores for both gene sets were highest in the ex-TRM cluster, confirming TRM-like identity. The ex-TRM cluster included all cGVHD patients and MC in similar proportions. We then compared abundance and gene expression of ex-TRM in cGVHD patients and MC. Ex-TRM as a fraction of CD8+ EM was similar between groups (0.08 vs 0.09). However, cGVHD ex-TRM showed upregulation of cytotoxicity genes (GZMB, GNLY, PRF1), NK-like (NKL) markers (KLRD1, FGFBP2, NKG7), and T-cell exhaustion (Tex)-associated genes (DUSP4, HAVCR2). The median module score for an external Tex gene signature was higher in cGVHD than MC (0.029 vs 0.016, p <0.001). DGE results were consistent after stratification by CMV serostatus. TCR analysis showed similar proportions of hyperexpanded (>100 cells/clonotype) and large (20-100 cells/clonotype) clones in ex-TRM between conditions (30% versus 28%). Normalized entropy scores for ex-TRM were identical (0.92), indicating comparable repertoire diversity. However, hyperexpanded and large clones in cGVHD exhibited even greater upregulation of cytotoxicity, NKL, and Tex genes by log2 fold change than the overall ex-TRM population. Finally, ImmuneWatch DETECT did not find viral epitope-specific clonotypes in ex-TRM from cGVHD patients, suggesting that expansion may reflect alloantigen recognition. In conclusion, we identified circulating ex-TRM during post-ASCT immune reconstitution using canonical TRM markers and module scoring. In cGVHD, ex-TRM had a distinct cytotoxic, NKL, and Tex gene signature, supporting possible antecedent tissue antigen exposure and pathogenicity. Future work will explore protein level validation and assess phenotypic and clonal overlap between ex-TRM and bona fide TRM in affected tissues. With further validation, ex-TRM may provide a surrogate for tissue-resident populations and the foundation for non-invasive biomarkers in cGVHD.

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Recent grants

• Chimeric Antigen Receptor T cell Therapy for Acute Myeloid Leukemia (AML)

  NIH · $839k · 2015–2021

• Enhancing Chimeric Antigen Receptor T Cell Therapies for HematologicMalignancies: Beyond CART 19

  NIH · $39.1M · 2017–2028

Frequent coauthors

• Carl H. June

  Parker Institute for Cancer Immunotherapy

  174 shared

• Marco Ruella

  University of Pennsylvania

  109 shared

• Stephan A. Grupp

  Children's Hospital of Philadelphia

  108 shared

• Olga Shestova

  University of Pennsylvania

  106 shared

• Noelle V. Frey

  California University of Pennsylvania

  102 shared

• Simon F. Lacey

  University of Pennsylvania

  86 shared

• Shannon L. Maude

  University of Pennsylvania

  75 shared

• Saad S. Kenderian

  Mayo Clinic in Arizona

  72 shared