About

James L. Riley, Ph.D., is a Professor of Microbiology at the University of Pennsylvania's Perelman School of Medicine. His research focuses on the signals that control primary human T cell activation and function, with particular attention to how these manipulations can be exploited to develop T cell therapies for HIV, autoimmune disease, and cancer. Dr. Riley's lab studies how to re-direct and expand human T regulatory cells for autoimmune disease treatment, utilizing TCR and CARs to redirect Tregs, and examining how these methods influence antigen suppression and T regulatory cell stability. His work also investigates how expanding T cells in different media affects their function and engraftment potential, as well as how external signaling and environmental factors perturb metabolic pathways. Additionally, Dr. Riley's research includes designing HIV-resistant, HIV-specific T cells as part of the HIV Cure effort. As a leader of the BEAT HIV Martin Delaney Collaboratory, his lab evaluates strategies to make T cells resistant to HIV entry and integration, and develops HIV-1 specific chimeric antigen receptors to assess their ability to control HIV replication in vitro and in humanized mouse models. His basic research findings have served as the basis for numerous Phase I adoptive T cell therapy clinical trials.

Research topics

• Medicine
• Internal medicine
• Immunology
• Intensive care medicine
• Oncology
• Virology
• Cancer research

Selected publications

• Rab5 improves CAR T cell efficacy via reducing fratricide and maintaining surface CAR levels

  The Journal of Experimental Medicine · 2026-03-27 · 1 citations

  articleSenior author

  We show continuous tumor exposure results in a loss of chimeric antigen receptor (CAR) T cell (CART) endocytic activity due to downregulation of Rab5. Loss of endocytic activity exacerbates the effects of trogocytosis, the bidirectional transfer of tumor target antigens and CARs between malignant cells and CARTs, resulting in CART dysfunction and fratricide. Constitutive expression of Rab5 within the CARTs reduced fratricide by reducing the amount of trogocytosed antigens on the cell surface, while simultaneously enhancing CAR availability through dissociation of CAR from target, recycling unbound CAR back to the plasma membrane, and limiting CAR capture by tumor cells. Rab5-expressing CARTs exhibited superior antitumor activity in both BCMA-CARTs isolated from the bone marrow of treated patients and mesothelin-specific CARTs in a solid tumor model. These studies uncover an unexpected relationship between endocytosis and CART function and suggest that pairing Rab5 with CAR expression could improve the clinical efficacy of CART therapy.

  PublisherDOI

• Supplementary Table 1 from Sequential Exposure to IL21 and IL15 During Human Natural Killer Cell Expansion Optimizes Yield and Function

  2025-11-26

  articleOpen access

  <p>Antibody list for 28-color Symphony A5 NK pane</p>

  PublisherOA PDFDOI

• CAR Binders Affect CAR T-cell Tonic Signaling, Durability, and Sensitivity to Target

  Cancer Immunology Research · 2025-04-29 · 4 citations

  articleOpen accessSenior author

  Patients can develop human anti-mouse immune responses against CD19-specific chimeric antigen receptor (CAR) T cells due to the use of a murine CD19-specific single-chain variable fragment to redirect T cells. We screened a yeast display library to identify an array of fully human CD19 single-chain variable fragment binders and performed a series of studies to select the most promising fully human CAR. We observed significant differences in the ability of CARs employing these CD19 binders to be expressed on the cell surface, induce tonic signaling, redirect T-cell function, mediate tumor killing, recognize lower levels of CD19 antigen, and maintain function upon continuous antigen exposure. From this initial analysis, CAR T cells using two binders (42 and 52) were selected for additional studies. Although CAR T cells using both binders controlled tumor growth well in vivo, we advanced a CAR construct using binder 42 for more advanced preclinical testing because of its greater similarity to binders based on the antibody FMC63, which is the murine antibody underlying four FDA-approved CD19-specific CAR T-cell therapies, and ability to robustly respond to tumors expressing lower levels of CD19. We found that this binder uniquely bound CD19 using distinct contact residues than FMC63 and with ∼40-fold lower affinity. CARs using binder 42 were non-inferior to those using the FMC63 binder in a mouse model of acute lymphoblastic leukemia, indicating that CAR T cells using binder 42 should be considered for clinical use.

  PublisherOA PDFDOI

• Supplementary Figure 3 from Sequential Exposure to IL21 and IL15 During Human Natural Killer Cell Expansion Optimizes Yield and Function

  2025-11-26

  articleOpen access

  <p>Figure S3. Expressions of activating receptors and cell death ligands on freshly isolated-NK cells and 2 expanded-NK cells.</p>

  PublisherOA PDFDOI

• Supplementary Data from CAR Binders Affect CAR T-cell Tonic Signaling, Durability, and Sensitivity to Target

  2025-06-04

  preprintOpen accessSenior author

  <p>Table S2</p>

  PublisherDOI

• Using Donor-Specific CAR Regulatory T-Cells to Promote Heart Allograft Tolerance in NHPs

  American Journal of Transplantation · 2025-08-01

  articleOpen access
  PublisherOA PDFDOI

• Optimal pairing of binder and co-stimulatory domains improves dual CART cell efficacy

  Molecular Therapy · 2025-08-06 · 2 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Chimeric antigen receptor T-cell therapy in patients with coexisting malignancy and autoimmune disease

  Blood · 2025-11-03

  articleOpen access

  Abstract Background: Chimeric antigen receptor (CART) therapies targeting CD19 or BCMA have shown great potential for treating autoimmune diseases (AD) in early-phase trials by depleting autoreactive B cells and plasma cells, resetting immune tolerance. While these findings suggest efficacy, current clinical evidence is limited to small, selected cohorts. We conducted a real-world analysis of patients (pts) with coexisting AD and relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL) or multiple myeloma (MM) treated with commercial CART19 or BCMA-CART. Methods: We studied 601 pts with r/r B-NHL or MM treated with commercial CART19 or BCMA-CART from 01/2018 to 12/2024 ( data cutoff: June 2025) at our institution. Antitumor responses were evaluated by Lugano criteria (NHL) and IMWG criteria (MM), and adverse events by ASTCT guidelines. AD was defined as active in the presence of serological markers and need for therapy. AD responses were based on symptom improvement and reduced immunosuppression; flares were defined as new/worsening symptoms or increased treatment need. Serum autoantibody profiling (Chang; Nat Commun. 2021) was performed on paired samples from 90 pts (51 CART19, 39 BCMA-CART) at day 0 and month 3 (M3) post-CART. Results: Overall, 403 (67%) pts had B-NHL and 198 (33%) MM. Median follow-up was 26 months. Forty-nine pts (8.2%) had a history of AD (36 with B-NHL; 13 with MM). ADs included rheumatoid arthritis (RA, n=12), autoimmune hemolytic anemia (AIHA) or immune thrombocytopenic purpura (n=9), sarcoidosis (n=9), systemic lupus erythematosus (SLE) or undifferentiated connective tissue disease (n=7), autoimmune thyroid disease (n=4), and inflammatory bowel disease (IBD, n=4). Less common ADs included psoriasis (n=2) and one case each of type 1 diabetes, ankylosing spondylitis, Sjogren's syndrome, uveitis, polymyalgia rheumatica, and autoimmune colitis. Four pts had multiple ADs. AD was more common in females (AD: 57% vs 35%, p<0.01). Within B-NHL and MM cohorts, baseline characteristics (age, histology, CART product, prior lines, transplant history) were similar between AD and non-AD groups.We first evaluated antitumor efficacy and safety of CART19 and BCMA-CART in patients with and without AD. Response rates, progression-free survival, overall survival, and incidence and severity of cytokine release syndrome and neurotoxicity were comparable (p>0.05).We then assessed the impact of CART on AD. Among 49 pts with AD, 2 B-NHL patients (4%)—1 with RA (RA#1) and 1 with SLE (SLE#1)—had active AD at CART19 infusion. Both were symptomatic and on treatment at CART infusion. RA#1 remained in AD remission until death from lymphoma progression 2.5 years post-CART. SLE#1 had a baseline ANA titer of 1:20,000, which decreased to 1:2,500 at M3 post-CART, accompanied by reduced DNA-associated antibodies (anti-histones, KU, P70/80, H2B, H2A/4, H3, H1, nucleolin; median fold change [FC] −70%, range −39% to −84%). In contrast, anti-Smith remained stable (FC −6%) while anti-SSB increased (FC +39%), suggesting selective depletion of pathogenic B-cell clones. SLE#1 experienced SLE relapse 2.3 years post-CART with isolated cutaneous involvement, while in remission of B-NHL.We then evaluated the 47 pts with AD in remission at the time of CART infusion. While 41 (87%) pts maintained AD remission, 6 (13%) pts (3 RA, 1 psoriasis, 1 IBD, and 1 AIHA) experienced AD flares within 3 months post-CART. All resolved with appropriate therapy: corticosteroids (n=2,RA), non-steroidal anti-inflammatory (n=1, RA), topical steroids plus phototherapy (psoriasis), mesalamine (IBD), or red blood cell transfusions (AIHA). To assess the broader impact of CART19 and BCMA-CART on the pt autoreactome (individual-specific autoantibody repertoire; Bodansky; JCI 2024), independently of AD diagnosis, we profiled 90 pts using a bead-based array targeting 52 autoantigens (Chang; Nat Commun. 2021). Both therapies modulated the autoreactome, with BCMA-CART inducing a significantly greater median reduction in autoantibodies (72% vs. 31%, p<0.001), supporting its broader potential in autoantibody-driven diseases. Conclusion: CART confirms durable AD control in real-world pts with coexisting NHL/MM. However, a subset of pts with AD in remission at infusion may experience post-CART AD flares, possibly due to the post-treatment inflammatory state, warranting close monitoring. Further studies are needed to understand flares' pathogenesis and their link with CART activity.

  PublisherOA PDFDOI

• Supplementary Data from CAR Binders Affect CAR T-cell Tonic Signaling, Durability, and Sensitivity to Target

  2025-06-04

  preprintOpen accessSenior author

  <p>Table S1</p>

  PublisherDOI

• Supplementary Figure 5 from Sequential Exposure to IL21 and IL15 During Human Natural Killer Cell Expansion Optimizes Yield and Function

  2025-11-26

  articleOpen access

  <p>Figure S5. Statistical analysis of the cytotoxicity of expanded-NK cells against different tumor targets and their degranulation.</p>

  PublisherOA PDFDOI

Recent grants

• NIH Grant P01AI080192

  NIH · $25.2M · 2015

• Molecular & Translational Immunotechnology Core

  NIH · $36.7M · 1999–2029

• Microphysiological systems for modeling autoimmunity in type 1 diabetes

  NIH · $2.3M · 2019–2024

• Modeling HIV CAR-T cell trafficking and persistence in Non-Human Primates

  NIH · $26.3M · 2020–2026

• NIH Grant R01CA113783

  NIH · $1.1M · 2010

Frequent coauthors

• Carl H. June

  Parker Institute for Cancer Immunotherapy

  330 shared

• Richard G. Carroll

  113 shared

• Bruce L. Levine

  University of Pennsylvania

  102 shared

• Bruce R. Blazar

  University of Minnesota

  58 shared

• Tatiana N. Golovina

  Fraunhofer USA Center for Molecular Biotechnology

  53 shared

• Richard V. Parry

  51 shared

• Craig B. Thompson

  45 shared

• Daniel C. St. Louis

  Henry M. Jackson Foundation

  43 shared

Labs

• Riley LabPI

Education

• PhD, Genetics and Molecular Biology

  Emory University

  1994

• BS, Molecular Biology

  Vanderbilt Health

  1989