Due to our extensive coverage of the Keystone Symposia meeting, we will not include any spotlights this week. We will report on the AACR Annual Meeting next week, so our regular digest will be back on April 24th.
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Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy Spotlight
Revach et al. showed that in ICB-treated patients with melanoma or NSCLC, CD8+ TIL expression of CD38, an ecto-enzyme involved in NAD+ catabolism, increased in parallel with co-inhibitory receptor and inversely with Tcf7 expression, and predicted ICB resistance. Cd38 was upregulated in exhausted CD8+ TILs of ICB-treated tumor-bearing mice, and Cd38 deletion reduced chronic stimulation-induced T cell dysfunction. CD38 blockade overcame ICB resistance in mouse- and patient-derived organotypic tumor spheroids. CD38 blockade or deletion reversed metabolic defects in exhausted T cells to allow Tcf7 expression, T cell function, and ICB response.
Contributed by Paula Hochman
Revach et al. showed that in ICB-treated patients with melanoma or NSCLC, CD8+ TIL expression of CD38, an ecto-enzyme involved in NAD+ catabolism, increased in parallel with co-inhibitory receptor and inversely with Tcf7 expression, and predicted ICB resistance. Cd38 was upregulated in exhausted CD8+ TILs of ICB-treated tumor-bearing mice, and Cd38 deletion reduced chronic stimulation-induced T cell dysfunction. CD38 blockade overcame ICB resistance in mouse- and patient-derived organotypic tumor spheroids. CD38 blockade or deletion reversed metabolic defects in exhausted T cells to allow Tcf7 expression, T cell function, and ICB response.
Contributed by Paula Hochman
ABSTRACT: A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma(1,2). T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance(3). Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD(+)) catabolism, is highly expressed in exhausted CD8(+) T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38(hi)CD8(+) T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD(+) pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD(+) axis in promoting T cell exhaustion and ICB resistance and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models.
Author Info: (1) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, M
Author Info: (1) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (2) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (3) Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. (4) Harvard Medical School, Boston, MA, USA. Department of Pathology, Boston Children's Hospital, Boston, MA, USA. (5) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (6) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (7) Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA. (8) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (9) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (10) Harvard Medical School, Boston, MA, USA. Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA, USA. (11) Harvard Medical School, Boston, MA, USA. Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA, USA. (12) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (13) Broad Institute of MIT and Harvard, Cambridge, MA, USA. (14) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (15) Teiko Bio, Salt Lake City, UT, USA. (16) Teiko Bio, Salt Lake City, UT, USA. (17) Teiko Bio, Salt Lake City, UT, USA. (18) Teiko Bio, Salt Lake City, UT, USA. (19) Teiko Bio, Salt Lake City, UT, USA. (20) Teiko Bio, Salt Lake City, UT, USA. (21) Teiko Bio, Salt Lake City, UT, USA. (22) Teiko Bio, Salt Lake City, UT, USA. (23) Teiko Bio, Salt Lake City, UT, USA. (24) Teiko Bio, Salt Lake City, UT, USA. Department of Otolaryngology-Head and Neck Cancer, University of California, San Francisco, San Francisco, CA, USA. Department of Microbiology & Immunology, University of California, San Francisco, San Francisco, CA, USA. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. Chan Zuckerberg Biohub, San Francisco, CA 94158; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (25) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (26) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (27) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (28) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (29) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (30) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (31) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. (32) Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (33) Harvard Medical School, Boston, MA, USA. Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (34) Harvard Medical School, Boston, MA, USA. Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. Department of Surgery, Cedars-Sinai Medical Center Los Angeles, CA, USA. (35) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (36) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (37) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (38) Harvard Medical School, Boston, MA, USA. Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA, USA. (39) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (40) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (41) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (42) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (43) Department of Pathology, Boston Children's Hospital, Boston, MA, USA. (44) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA. (45) Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel. (46) Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Cambridge, MA, USA. (47) Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. Department of Pathology, Boston Children's Hospital, Boston, MA, USA. (48) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (49) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA. (50) Mass General Cancer Center, Krantz Family Center for Cancer Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses Spotlight
Kelly, Landon, and Zaidi et al. reported the safety, feasibility, and efficacy of neoadjuvant nivolumab (Arm A) or nivolumab plus relatlimab (Arm B) combined with chemoradiotherapy in patients with resectable stage II/stage III gastroesophageal cancer. The primary endpoint of safety for Arm A was met, but required an amendment to mitigate toxicity in Arm B. The pCR rate was 40% for Arm A and 21.4% for Arm B, and the 2-year OS rates were 82.6% in Arm A and 93.8% in Arm B. Circulating tumor DNA (ctDNA) analysis was predictive of tumor regression, RFS, and OS, outperforming pCR and MPR. Neoantigen-specific T cell responses paralleled ctDNA kinetics.
Contributed by Shishir Pant
Kelly, Landon, and Zaidi et al. reported the safety, feasibility, and efficacy of neoadjuvant nivolumab (Arm A) or nivolumab plus relatlimab (Arm B) combined with chemoradiotherapy in patients with resectable stage II/stage III gastroesophageal cancer. The primary endpoint of safety for Arm A was met, but required an amendment to mitigate toxicity in Arm B. The pCR rate was 40% for Arm A and 21.4% for Arm B, and the 2-year OS rates were 82.6% in Arm A and 93.8% in Arm B. Circulating tumor DNA (ctDNA) analysis was predictive of tumor regression, RFS, and OS, outperforming pCR and MPR. Neoantigen-specific T cell responses paralleled ctDNA kinetics.
Contributed by Shishir Pant
ABSTRACT: Gastroesophageal cancer dynamics and drivers of clinical responses with immune checkpoint inhibitors (ICI) remain poorly understood. Potential synergistic activity of dual programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) inhibition may help improve immunotherapy responses for these tumors. We report a phase Ib trial that evaluated neoadjuvant nivolumab (Arm A, n = 16) or nivolumab-relatlimab (Arm B, n = 16) in combination with chemoradiotherapy in 32 patients with resectable stage II/stage III gastroesophageal cancer together with an in-depth evaluation of pathological, molecular and functional immune responses. Primary endpoint was safety; the secondary endpoint was feasibility; exploratory endpoints included pathological complete (pCR) and major pathological response (MPR), recurrence-free survival (RFS) and overall survival (OS). The study met its primary safety endpoint in Arm A, although Arm B required modification to mitigate toxicity. pCR and MPR rates were 40% and 53.5% for Arm A and 21.4% and 57.1% for Arm B. Most common adverse events were fatigue, nausea, thrombocytopenia and dermatitis. Overall, 2-year RFS and OS rates were 72.5% and 82.6%, respectively. Higher baseline programmed cell death ligand 1 (PD-L1) and LAG-3 expression were associated with deeper pathological responses. Exploratory analyses of circulating tumor DNA (ctDNA) showed that patients with undetectable ctDNA post-ICI induction, preoperatively and postoperatively had a significantly longer RFS and OS; ctDNA clearance was reflective of neoantigen-specific T cell responses. Our findings provide insights into the safety profile of combined PD-1 and LAG-3 blockade in gastroesophageal cancer and highlight the potential of ctDNA analysis to dynamically assess systemic tumor burden during neoadjuvant ICI that may open a therapeutic window for future intervention. ClinicalTrials.gov registration: NCT03044613 .
Author Info: (1) The Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA. ronan.kelly@bswhealth.org. (2) The Sidney Kimmel Comprehensive Cancer Center, Johns Hop
Author Info: (1) The Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA. ronan.kelly@bswhealth.org. (2) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (3) Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA. (4) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute of Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (5) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (6) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (7) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (8) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (9) Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (10) Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA. (11) Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (12) Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (13) Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (14) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute of Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (15) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (16) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (17) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (18) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (19) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (20) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (21) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. (22) Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA. (23) Allegheny Health Network Cancer Institute, Allegheny Health Network, Pittsburgh, PA, USA. (24) Department of Gastroenterology & Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (25) Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (26) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute of Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (27) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg-Kimmel Institute of Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (28) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. (29) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (30) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu. The Bloomberg-Kimmel Institute of Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu. Lung Cancer Precision Medicine Center of Excellence, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vanagno1@jhmi.edu. (31) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. vklam@jhmi.edu.
Targeting refractory/recurrent neuroblastoma and osteosarcoma with anti-CD3_anti-GD2 bispecific antibody armed T cells
BACKGROUND: The survival benefit observed in children with neuroblastoma (NB) and minimal residual disease who received treatment with anti-GD2 monoclonal antibodies prompted our investigation into the safety and potential clinical benefits of anti-CD3_anti-GD2 bispecific antibody (GD2Bi) armed T cells (GD2BATs). Preclinical studies demonstrated the high cytotoxicity of GD2BATs against GD2+cell lines, leading to the initiation of a phase I/II study in recurrent/refractory patients. METHODS: The 3+3_dose escalation phase I study (NCT02173093) encompassed nine evaluable patients with NB (n=5), osteosarcoma (n=3), and desmoplastic small round cell tumors (n=1). Patients received twice-weekly infusions of GD2BATs at 40, 80, or 160_10(6) GD2BATs/kg/infusion complemented by daily interleukin-2 (300,000 IU/m(2)) and twice-weekly granulocyte macrophage colony-stimulating factor (250 µg/m(2)). The phase II segment focused on patients with NB at the dose 3 level of 160_10(6) GD2BATs/kg/infusion. RESULTS: Of the 12 patients enrolled, 9 completed therapy in phase I with no dose-limiting toxicities. Mild and manageable cytokine release syndrome occurred in all patients, presenting as grade 2-3 fevers/chills, headaches, and occasional hypotension up to 72 hours after GD2BAT infusions. GD2-antibody-associated pain was minimal. Median overall survival (OS) for phase I and the limited phase II was 18.0 and 31.2 months, respectively, with a combined OS of 21.1 months. A phase I NB patient had a complete bone marrow response with overall stable disease. In phase II, 10 of 12 patients were evaluable: 1 achieved partial response, and 3 showed clinical benefit with prolonged stable disease. Over 50% of evaluable patients exhibited augmented immune responses to GD2+targets post-GD2BATs, as indicated by interferon-gamma (IFN-_) EliSpots, Th1 cytokines, and/or chemokines. CONCLUSIONS: This study demonstrated the safety of GD2BATs up to 160_10(6)_cells/kg/infusion. Coupled with evidence of post-treatment endogenous immune responses, our findings support further investigation of GD2BATs in larger phase II clinical trials.
Author Info: (1) St. Christopher's Hospital for Children, Philadelphia, Pennsylvania, USA yankelevic@gmail.com LGL4F@uvahealth.org. Children's Hospital of Michigan, Detroit, Michigan, USA. (2)
Author Info: (1) St. Christopher's Hospital for Children, Philadelphia, Pennsylvania, USA yankelevic@gmail.com LGL4F@uvahealth.org. Children's Hospital of Michigan, Detroit, Michigan, USA. (2) University of Virginia Cancer Center, Charlottesville, Virginia, USA. (3) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (4) Children's Hospital of Michigan, Detroit, Michigan, USA. (5) Children's Hospital of Michigan, Detroit, Michigan, USA. (6) Children's Hospital of Michigan, Detroit, Michigan, USA. (7) University of Virginia Cancer Center, Charlottesville, Virginia, USA. (8) University of Virginia Cancer Center, Charlottesville, Virginia, USA. (9) University of Virginia Cancer Center, Charlottesville, Virginia, USA. (10) University of Virginia Cancer Center, Charlottesville, Virginia, USA. (11) University of Virginia Cancer Center, Charlottesville, Virginia, USA. (12) Wistar Institute, Philadelphia, Pennsylvania, USA. (13) Karmanos Cancer Institute, Detroit, Michigan, USA. (14) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (15) University of Virginia Cancer Center, Charlottesville, Virginia, USA yankelevic@gmail.com LGL4F@uvahealth.org.
CD155 as an emerging target in tumor immunotherapy
CD155 is an immunoglobulin-like protein overexpressed in almost all the tumor cells, which not only promotes proliferation, adhesion, invasion, and migration of tumor cells, but also regulates immune responses by interacting with TIGIT, CD226 or CD96 receptors expressed on several immune cells, thereby modulating the functionality of these cellular subsets. As a novel immune checkpoint, the inhibition of CD155/TIGIT, either as a standalone treatment or in conjunction with other immune checkpoint inhibitors, has demonstrated efficacy in managing advanced solid malignancies. In this review, we summarize the intricate relationship between on tumor surface CD155 and its receptors, with further discussion on how they regulate the occurrence of tumor immune escape. In addition, novel therapeutic strategies and clinical trials targeting CD155 and its receptors are summarized, providing a strong rationale and way forward for the development of next-generation immunotherapies.
Author Info: (1) State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of He
Author Info: (1) State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. (2) Henan Engineering Research Center for Application & Translation of Precision Clinical Pharmacy, Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, China. (3) State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. (4) State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. (5) State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. Electronic address: yichaozheng@zzu.edu.cn. (6) State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Key Laboratory of Henan Province for Drug Quality and Evaluation, XNA Platform, School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. Electronic address: liuhuimin@zzu.edu.cn.
The role of extracellular vesicle immune checkpoints in cancer
Immune checkpoints (ICPs) play a crucial role in regulating the immune response. In the tumor, malignant cells can hijack the immunosuppressive effects of inhibitory ICPs to promote tumor progression. Extracellular vesicles (EVs) are produced by a variety of cells and contain bioactive molecules on their surface or within their lumen. The expression of ICPs has also been detected on EVs. In vitro and in vivo studies have shown that extracellular vesicle immune checkpoints (EV ICPs) have immunomodulatory effects and are involved in tumor immunity. EV ICPs isolated from the peripheral blood of cancer patients are closely associated with the tumor progression and the prognosis of cancer patients. Blocking inhibitory ICPs has been recognized as an effective strategy in cancer treatment. However, the efficacy of immune checkpoint inhibitors (ICIs) in cancer treatment is hindered by the emergence of therapeutic resistance, which limit their widespread use. Researchers have demonstrated that EV ICPs are correlated with clinical response to ICIs therapy and were involved in therapeutic resistance. Therefore, it's essential to investigate the immunomodulatory effects, underlying mechanisms, and clinical significance of EV ICPs in cancer. This review aims to comprehensively explore these aspects. We have provided a comprehensive description of the cellular origins, immunomodulatory effects, and clinical significance of EV ICPs in cancer, based on relevant studies.
Author Info: (1) Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China. (2) Department of Laborat
Author Info: (1) Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China. (2) Department of Laboratory Medicine, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing Jiangsu, China. (3) Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China. (4) Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China.
Human leukocyte antigen (HLA) restriction of conventional T-cell targeting introduces complexity in generating T-cell therapy strategies for patients with cancer with diverse HLA-backgrounds. A subpopulation of atypical, major histocompatibility complex-I related protein 1 (MR1)-restricted T-cells, distinctive from mucosal-associated invariant T-cells (MAITs), was recently identified recognizing currently unidentified MR1-presented cancer-specific metabolites. It is hypothesized that the MC.7.G5 MR1T-clone has potential as a pan-cancer, pan-population T-cell immunotherapy approach. These cells are irresponsive to healthy tissue while conferring T-cell receptor(TCR) dependent, HLA-independent cytotoxicity to a wide range of adult cancers. Studies so far are limited to adult malignancies. Here, we investigated the potential of MR1-targeting cellular therapy strategies in pediatric cancer. Bulk RNA sequencing data of primary pediatric tumors were analyzed to assess MR1 expression. In vitro pediatric tumor models were subsequently screened to evaluate their susceptibility to engineered MC.7.G5 TCR-expressing T-cells. Targeting capacity was correlated with qPCR-based MR1 mRNA and protein overexpression. RNA expression of MR1 in primary pediatric tumors varied widely within and between tumor entities. Notably, embryonal tumors exhibited significantly lower MR1 expression than other pediatric tumors. In line with this, most screened embryonal tumors displayed resistance to MR1T-targeting in vitro MR1T susceptibility was observed particularly in pediatric leukemia and diffuse midline glioma models. This study demonstrates potential of MC.7.G5 MR1T-cell immunotherapy in pediatric leukemias and diffuse midline glioma, while activity against embryonal tumors was limited. The dismal prognosis associated with relapsed/refractory leukemias and high-grade brain tumors highlights the promise to improve survival rates of children with these cancers.
Author Info: (1) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (2) Prinses Maxima Centrum vo
Author Info: (1) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (2) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (3) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (4) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. Center of Pediatric Hematology & Oncology, University of Catania, Catania, Italy. (5) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (6) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. (7) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. (8) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. (9) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (10) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (11) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (12) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. (13) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. Oncode Institute, Utrecht, The Netherlands. (14) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (15) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (16) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (17) Center of Pediatric Hematology & Oncology, University of Catania, Catania, Italy. (18) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (19) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. (20) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands. Department of Hematology, UMC Utrecht, Utrecht, The Netherlands. (21) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (22) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. Oncode Institute, Utrecht, The Netherlands. (23) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (24) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (25) Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands. (26) Prinses Maxima Centrum voor Kinderoncologie, Utrecht, The Netherlands S.Nierkens-2@prinsesmaximacentrum.nl. Center for Translational Immunology, UMC Utrecht, Utrecht, The Netherlands.
Engineered extracellular vesicles enable high-efficient delivery of intracellular therapeutic proteins
Developing an intracellular delivery system is of key importance in the expansion of protein-based therapeutics acting on cytosolic or nuclear targets. Recently, extracellular vesicles (EVs) have been exploited as next-generation delivery modalities due to their natural role in intercellular communication and biocompatibility. However, fusion of protein of interest to a scaffold represents a widely-used strategy for cargo enrichment in EVs, which could compromise t the stability and functionality of cargo. Herein, we report intracellular delivery via EV-based approach (IDEA) that efficiently packages and delivers native proteins both in vitro and in vivo without the use of a scaffold. As a proof-of-concept, we applied the IDEA to deliver cyclic GMP-AMP synthase (cGAS), an innate immune sensor. The results showed that cGAS-carrying EVs activated interferon signaling and elicited enhanced antitumor immunity in multiple syngeneic tumor models. Combining cGAS EVs with immune checkpoint inhibition further synergistically boosted antitumor efficacy in vivo. Mechanistically, scRNA-seq demonstrated that cGAS EVs mediated significant remodelling of intratumoral microenvironment, revealing a pivotal role of infiltrating neutrophils in the antitumor immune milieu. Collectively, IDEA, as a universal and facile strategy, can be applied to expand and advance the development of protein-based therapeutics.
Author Info: (1) Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Blo
Author Info: (1) Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei 230036, China. School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (2) Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei 230036, China. School of Biomedical Engineering, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China. (3) School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (4) School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (5) School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (6) School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (7) School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. (8) Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei 230036, China. (9) Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei 230036, China. (10) Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei 230036, China. School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China. School of Biomedical Engineering, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China. (11) Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China. Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei 230036, China. School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.
An IRF2-Expressing Oncolytic Virus Changes the Susceptibility of Tumor Cells to Antitumor T cells and Promotes Tumor Clearance
Interferon regulatory factor 1 (IRF1) can promote antitumor immunity. However, we have shown previously that in the tumor cell, IRF1 can promote tumor growth, and IRF1-deficient tumor cells exhibit severely restricted tumor growth in several syngeneic mouse tumor models. Here, we investigate the potential of functionally modulating IRF1 to reduce tumor progression and prolong survival. Using inducible IRF1 expression, we established that it is possible to regulate IRF1 expression to modulate tumor progression in established B16-F10 tumors. Expression of IRF2, which is a functional antagonist of IRF1, down-regulated IFN_-induced expression of inhibitory ligands, up-regulated MHC-related molecules, and slowed tumor growth and extended survival. We characterized the functional domain(s) of IRF2 needed for this antitumor activity, showing that a full-length IRF2 was required for its antitumor functions. Finally, using an oncolytic vaccinia virus as a delivery platform, we showed that IRF2-expressing vaccinia virus suppressed tumor progression and prolonged survival in multiple tumor models. These results suggest the potency of targeting IRF1 and using IRF2 to modulate immunotherapy.
Author Info: (1) University of Pittsburgh, Pittsburgh, PA, United States. (2) University of Pittsburgh, Pittsburgh, PA, United States. (3) University of Pittsburgh, Pittsburgh, PA, United State
Author Info: (1) University of Pittsburgh, Pittsburgh, PA, United States. (2) University of Pittsburgh, Pittsburgh, PA, United States. (3) University of Pittsburgh, Pittsburgh, PA, United States. (4) University of Pittsburgh, Pittsburgh, PA, United States. (5) University of Pittsburgh, Pittsburgh, PA, United States.
Melanoma extracellular vesicles inhibit tumor growth and metastasis by stimulating CD8 T cells
Tumor cell-derived extracellular vesicles (EVs) play a crucial role in mediating immune responses by carrying and presenting tumor antigens. Here, we suggested that melanoma EVs triggered cytotoxic CD8 T cell-mediated inhibition of tumor growth and metastasis. Our results indicated that immunization of mice with melanoma EVs inhibited melanoma growth and metastasis while increasing CD8 T cells and serum interferon _ (IFN-_) in vivo. In vitro experiments showed that melanoma EV stimulates dendritic cells (DCs) maturation, and mature dendritic cells induce T lymphocyte activation. Thus, tumor cell-derived EVs can generate anti-tumor immunity in a prophylactic setting and may be potential candidates for cell-free tumor vaccines.
Author Info: (1) State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laborato
Author Info: (1) State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China. (2) State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China. (3) State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China. (4) State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China. (5) State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China; National Engineering Research Center of Ultrasound Medicine, Chongqing 401121, China. Electronic address: lqfang06@163.com. (6) State Key Laboratory of Ultrasound in Medicine and Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Biomedical Engineering, Chongqing Medical University, Chongqing 400016, China. Electronic address: sajinbai@cqmu.edu.cn.
