About

Carl H. June, M.D., is the Richard W. Vague Professor in Immunotherapy at the University of Pennsylvania, Department of Pathology and Laboratory Medicine. He is also the Director of the Translational Research Program, the Center for Cellular Immunotherapies, and the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania. His research expertise focuses on lymphocyte biology, with a major translational emphasis on ex vivo T-cell engineering for cancer and HIV cell-based therapies. The June Laboratory is responsible for developing new chimeric antigen receptors (CARs) and vectors for current and proposed indications, fostering the development of students in doctoral and post-doctoral programs, and translating laboratory insights into safe and effective cancer therapies. The lab collaborates with faculty members interested in advancing biologically-focused research into clinical trials and works on enhancing the natural immune system's ability to recognize and eliminate tumor cells. His work is integrated with the broader mission of the Leonard and Madlyn Abramson Family Cancer Research Institute at the Abramson Cancer Center, which combines research, education, and patient care.

Research topics

• Immunology
• Medicine
• Internal medicine
• Biology
• Cancer research
• Oncology
• Genetics
• Bioinformatics
• Pharmacology
• Cell biology
• Chemistry
• Computational biology
• Biochemistry
• Molecular biology
• Intensive care medicine
• Surgery

Selected publications

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

  Blood · 2026-04-16

  article

  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.

  PublisherDOI

• A generalizable system for antigenic peptide targeting across HLA-I allotypes

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-22

  articleOpen access

  T cell receptors (TCRs) and TCR-mimicking antibodies recognize peptide antigens in the context of specific Human Leucocyte Antigen (HLA-I) allotypes, and the extreme polymorphism of the HLA locus limits the breadth of immunotherapy development. Key barriers include divergent molecular surfaces on HLA proteins and differences in the peptide structure. As a result, existing modalities cannot confer therapeutic coverage across patients of divergent genetic backgrounds. Here, we develop an approach which combines a peptide conformational prediction tool, PepPred, with a cross-HLA binding protein engineering system, TRACeR-I1, to outline a generalized framework for developing binders (xTRACeRs) with compatibility across HLA allotypes while maintaining high levels of specificity towards the peptide antigen. We use our system to develop and validate xTRACeRs against clinically relevant, established peptide antigens presented across common alleles within five HLA-A/B/C supertypes2. Cryo-EM structures of xTRACeR-pHLA complexes for an oncofetal antigen from PRAME and a neuroblastoma-specific peptide from PHOX2B reveal effective mechanisms to navigate polymorphic HLA surface residues, and extensive interactions with the peptide. We implemented these two xTRACeRs as Chimeric Antigen Receptor (CAR) T cells and demonstrated their potent killing efficacy and specificity. Overcoming restriction across HLA supertypes lifts a key barrier in HLA-targeted immunotherapy by expanding patient coverage.

  PublisherDOI

• Cell-derived Nanoparticles Provide a Robust Platform to Manufacture Therapeutic T cells.

  Research Square · 2026-02-04

  preprintOpen access
  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 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

• 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

  <p>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.</p>

  PublisherDOI

• DR5 CAR-T cells target melanoma and suppress MDSCs with minimal toxicity

  Molecular Therapy · 2025-12-11

  articleOpen access
  PublisherOA PDFDOI

• IL-9 signaling redirects CAR T cell fate toward CD8+ memory and CD4+ cycling states, enhancing antitumor efficacy

  Immunity · 2025-11-21 · 7 citations

  articleSenior author
  PublisherDOI

• Cytokine receptor armored CAR-T cells enable robust T cell expansion and function in the absence of lymphodepletion

  Blood · 2025-11-03

  articleOpen access

  Abstract Chimeric antigen receptor (CAR) T cell therapy is emerging as a promising approach for oncology and autoimmune diseases. However, its broad clinical translation remains limited by the reliance on lymphodepleting chemotherapy (e.g., fludarabine/cyclophosphamide), which is particularly undesirable in non-malignant settings due to its associated toxicity. To overcome this barrier, we aimed to engineer CAR-T cells capable of robust in vivo expansion and persistence without lymphodepletion. We systematically screened 19 underexplored immunomodulatory cytokines across the common γ-chain, β-chain, IL-6, and IL-10 families to identify candidates that enhance CAR-T function while minimizing systemic toxicity. This screen revealed IL27 with potent in vivo efficacy and favorable safety profiles in murine models. To harness this cytokine signal in a cell-intrinsic manner, we engineered CAR T cells with constitutively active gp130 (cGP130)， a synthetic active receptor for IL27. This modification enhanced CAR T cell anti-tumor efficacy in vivo in the tumor bearing mice by 10X. In addition, CAR T cells with this receptor modification did not exhibit uncontrolled growth as confirmed by cytokine-independent growth assays and in vivo expansion kinetics. To test whether this receptor-driven proliferation could eliminate the need for lymphodepletion, we constructed CD20-targeting CAR T cells from cynomolgus T cells armed with cGP130，so that the T cell could proliferate upon the stimulation of CD20 antigen. We infused multiple cells together into a single recipient without lymphodepletion and monitored the CART expansion via ddPCR. CART cells without modification had modest engraftment while CAR T cells expressing IL27 and cGP130 demonstrated robust expansion in non-human primates with a three-fold increase in Cmax. In addition, we did not observe toxicity or inflammatory reactions in the NHP. These findings highlight IL27 and its receptor pathway as a promising strategy to optimize CAR T cell therapy. By eliminating the need for lymphodepletion, this approach could broaden the safe application of CAR T cells to autoimmune diseases and other non-malignant settings. Our results lay the groundwork for future clinical trials aimed at enhancing CAR T cell expansion, persistence, and therapeutic efficacy in the absence of lymphodepleting chemotherapy.

  PublisherOA PDFDOI

• 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

Recent grants

• NIH Grant P50CA083638

  NIH · $4.3M · 2015

• NIH Grant U01AI104400

  NIH · $5.8M · 2018

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

  NIH · $3.4M · 2017–2022

• Engineering the Next Generation of T Cells

  NIH · $13.8M · 2019–2024

• NIH Grant R01CA105216

  NIH · $1.5M · 2010

Frequent coauthors

• Bruce L. Levine

  University of Pennsylvania

  927 shared

• Stephan A. Grupp

  Children's Hospital of Philadelphia

  336 shared

• James L. Riley

  University of Pennsylvania

  330 shared

• Simon F. Lacey

  University of Pennsylvania

  301 shared

• J. Joseph Melenhorst

  Cleveland Clinic

  259 shared

• John Scholler

  University of Pennsylvania

  193 shared

• Joseph A. Fraietta

  University of Pennsylvania

  182 shared

• Saar Gill

  University of Pennsylvania

  174 shared

Labs

• June LaboratoryPI

Awards & honors

• Richard W. Vague Professor in Immunotherapy
• Director, Translational Research Program
• Director, Center for Cellular Immunotherapies
• Director, Parker Institute for Cancer Immunotherapy at the U…