ACIR Journal Articles

CX3CL1 release during immunogenic apoptosis is associated with enhanced anti-tumour immunity

(1) Naessens F (2) Demuynck R (3) Vershinina O (4) Efimova I (5) Saviuk M (6) De Smet G (7) Mishchenko TA (8) Vedunova MV (9) Krysko O (10) Catanzaro E (11) Krysko DV

Frontiers in immunology - Open Access | Free PMC Article

(1) Naessens F (2) Demuynck R (3) Vershinina O (4) Efimova I (5) Saviuk M (6) De Smet G (7) Mishchenko TA (8) Vedunova MV (9) Krysko O (10) Catanzaro E (11) Krysko DV

Frontiers in immunology - Open Access | Free PMC Article

INTRODUCTION: Immunogenic cell death (ICD) has emerged as a novel option for cancer immunotherapy. The key determinants of ICD encompass antigenicity (the presence of antigens) and adjuvanticity, which involves the release of damage-associated molecular patterns (DAMPs) and various cytokines and chemokines. CX3CL1, also known as neurotactin or fractalkine, is a chemokine involved in cellular signalling and immune cell interactions. CX3CL1 has been denoted as a "find me" signal that stimulates chemotaxis of immune cells towards dying cells, facilitating efferocytosis and antigen presentation. However, in the context of ICD, it is uncertain whether CX3CL1 is an important mediator of the effects of ICD. METHODS: In this study, we investigated the intricate role of CX3CL1 in immunogenic apoptosis induced by mitoxantrone (MTX) in cancer cells. The Luminex xMAP technology was used to quantify murine cytokines, chemokines and growth factors to identify pivotal regulatory cytokines released by murine fibrosarcoma MCA205 and melanoma B16-F10 cells undergoing ICD. Moreover, a murine tumour prophylactic vaccination model was employed to analyse the effect of CX3CL1 on the activation of an adaptive immune response against MCA205 cells undergoing ICD. Furthermore, thorough analysis of the TCGA-SKCM public dataset from 98 melanoma patients revealed the role of CX3CL1 and its receptor CX3CR1 in melanoma patients. RESULTS: Our findings demonstrate enhanced CX3CL1 release from apoptotic MCA205 and B16-F10 cells (regardless of the cell type) but not if they are undergoing ferroptosis or accidental necrosis. Moreover, the addition of recombinant CX3CL1 to non-immunogenic doses of MTX-treated, apoptotically dying cancer cells in the murine prophylactic tumour vaccination model induced a robust immunogenic response, effectively increasing the survival of the mice. Furthermore, analysis of melanoma patient data revealed enhanced survival rates in individuals exhibiting elevated levels of CD8+ T cells expressing CX3CR1. CONCLUSION: These data collectively underscore the importance of the release of CX3CL1 in eliciting an immunogenic response against dying cancer cells and suggest that CX3CL1 may serve as a key switch in conferring immunogenicity to apoptosis.

Author Info: (1) Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent Universit

Author Info: (1) Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. Cancer Research Institute Ghent, Ghent, Belgium. (2) Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. Cancer Research Institute Ghent, Ghent, Belgium. (3) Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia. (4) Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. Cancer Research Institute Ghent, Ghent, Belgium. (5) Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. Cancer Research Institute Ghent, Ghent, Belgium. (6) Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. (7) Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia. (8) Institute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia. (9) Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. (10) Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. Cancer Research Institute Ghent, Ghent, Belgium. (11) Cell Death Investigation and Therapy Laboratory, Anatomy and Embryology Unit, Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium. Cancer Research Institute Ghent, Ghent, Belgium.

Citation: Front Immunol 2024 15:1396349 Epub07/01/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39011040

Robust anti-tumor immunity through the integration of targeted lipid nanoparticle-based mRNA nanovaccines with PD-1/PD-L1 blockade

(1) Jin C (2) Zhang Y (3) Li B (4) Gao T (5) Wang B (6) Hua P

Materials today. Bio - Open Access | Free PMC Article

(1) Jin C (2) Zhang Y (3) Li B (4) Gao T (5) Wang B (6) Hua P

Materials today. Bio - Open Access | Free PMC Article

Tumor mRNA vaccines present a personalized approach in cancer immunotherapy, encoding distinct tumor antigens to evoke robust immune responses and offering the potential against emerging tumor variants. Despite this, the clinical advancement of tumor mRNA vaccines has been hampered by their limited delivery capacity and inefficient activation of antigen-presenting cells (APCs). Herein, we employed microfluidics technology to engineer mannose-modified lipid-based nanovaccines for specifically targeting APCs. The encapsulation process efficiently entrapped the cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) agonist along with mRNA encoding antigens. The targeted nanovaccines (TNVs) exhibited a narrow particle size distribution, ensuring consistent and efficient delivery. These TNVs significantly enhanced gene expression of mRNA, facilitating antigen presentation and immune activation. When compared to non-targeted nanovaccines, TNVs outperformed in terms of antigen presentation and immune activation. Furthermore, the combination of anti-PD-L1 antibodies with TNVs elicited a synergistic anti-tumor effect. This was attributed to the anti-PD-L1 antibodies' ability to overcome the immune suppression of tumor cells. Our findings suggest that the combination treatment elicited the most robust anti-tumor immune activation and immune memory effect. These results indicate that integrating tumor mRNA vaccines with immune checkpoint inhibitors or other immunostimulatory agents may be crucial for enhancing the immune response.

Author Info: (1) Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, Jilin Province, 130022, China. (2) Department of Thoracic Surgery, The Second Hospital of Ji

Author Info: (1) Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, Jilin Province, 130022, China. (2) Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, Jilin Province, 130022, China. (3) Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, Jilin Province, 130022, China. (4) College of Clinical Medicine, Jiamusi University, Jiamusi, Heilongjiang Province, 154007, China. (5) Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, Jilin Province, 130022, China. (6) Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, Jilin Province, 130022, China.

Citation: Mater Today Bio 2024 Aug 27:101136 Epub06/22/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39015802

Beyond Cytotoxic Potency: Disposition Features Required to Design ADC Payload

(1) Sun H (2) Wienkers LC (3) Lee A

Xenobiotica; the fate of foreign compounds in biological systems

(1) Sun H (2) Wienkers LC (3) Lee A

Xenobiotica; the fate of foreign compounds in biological systems

Antibody-drug conjugates (ADCs) have demonstrated impressive clinical usefulness in treating several types of cancer, with the notion of widening of the therapeutic index of the cytotoxic payload through the minimization of the systemic toxicity. Therefore, choosing the most appropriate payload molecule is a particularly important part of the early design phase of ADC development, especially given the highly competitive environment ADCs find themselves in today. The focus of the current review is to describe critical attributes/considerations needed in the discovery and ultimately development of cytotoxic payloads in support of ADC design. In addition to potency, several key dispositional characteristics including solubility, permeability and bystander effect, pharmacokinetics, metabolism, and drug-drug interactions, are described as being an integral part of the integrated activities required in the design of clinically safe and useful ADC therapeutic agents.

Author Info: (1) Clinical Pharmacology and Translational Sciences, Pfizer Oncology Division, Pfizer, Inc., Bothell, Washington 98021. (2) Clinical Pharmacology and Translational Sciences, Pfize

Author Info: (1) Clinical Pharmacology and Translational Sciences, Pfizer Oncology Division, Pfizer, Inc., Bothell, Washington 98021. (2) Clinical Pharmacology and Translational Sciences, Pfizer Oncology Division, Pfizer, Inc., Bothell, Washington 98021. (3) Clinical Pharmacology and Translational Sciences, Pfizer Oncology Division, Pfizer, Inc., Bothell, Washington 98021.

Citation: Xenobiotica 2024 Jul 17 1-25 Epub07/17/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39017706

Crosstalk between Circadian Rhythm Dysregulation and Tumorigenesis, Tumor Metabolism and Tumor Immune Response

(1) Zhu Y (2) Zheng Y (3) Dai R (4) Gu X

Aging and disease

(1) Zhu Y (2) Zheng Y (3) Dai R (4) Gu X

Aging and disease

Circadian rhythm is a self-regulating 24-hour system that synchronizes with the day and night cycle in organisms. The regulation of this system is controlled by clock genes, which function to harmoniously express molecular levels that facilitate the orderly coordination of various cellular processes, such as sleep, metabolism, endocrine function, cell proliferation and immunity. The root cause of tumorigenesis is that the body loses its normal regulation of cell growth at the genetic level. Long-term disruptions in circadian rhythms caused by factors such as shift work, jet lag, and unstable sleep patterns can impact cellular health, leading to various health problems, including cancer. Circadian rhythm controls most cellular functions related to cancer progression, which has a significant impact on the ability of immune cells to detect cancer cells and promote their clearance and has crucial implication for future tumor immunotherapy. This article aims to review the crosstalk between dysregulation of circadian rhythm and tumorigenesis, tumor metabolism, and immune response. Additionally, we discuss the role of circadian rhythm disruption in tumor therapy, highlighting its potential to optimize treatment timing and improve therapeutic outcomes.

Author Info: (1) Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China. Cancer

Author Info: (1) Department of Oncology, Shanghai Medical College of Fudan University, Shanghai, China. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China. Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China. Institute of Pathology, Fudan University, Shanghai, China. (2) Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Shanghai, China. (3) School of Medicine, Southeast University, Nanjing, China. (4) Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.

Citation: Aging Dis 2024 Jul 2 Epub07/02/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39012661

Chronological Management of Adjuvant Effect for Optimized mRNA Vaccine Inspired by Natural Virus Infection

(1) Lou Z (2) Shi Y (3) Guo X (4) Jin Z (5) Huang J (6) Hu Y (7) Liu X (8) Zhu J (9) Kuang R (10) You J

ACS nano

(1) Lou Z (2) Shi Y (3) Guo X (4) Jin Z (5) Huang J (6) Hu Y (7) Liu X (8) Zhu J (9) Kuang R (10) You J

ACS nano

The efficacy and safety of mRNA vaccines both rely on a fine-tuning of specific humoral and cellular immune responses. Instead of adjustments in vaccine component, we proposed a concept of chronological management of adjuvant effect to modulate the adaptive immune potency and preference inspired by natural virus infection. By simulating type I interferon expression dynamics during viral infection, three vaccine strategies employing distinct exposure sequences of adjuvant and mRNA have been developed, namely Precede, Coincide, and Follow. Follow, the strategy of adjuvant administration following mRNA, effectively suppressed tumor progression, which was attributed to enhanced mRNA translation, augmented p-MHC I expression, and elevated CD8(+) T cell response. Meanwhile, Follow exhibited improved biosafety, characterized by reduced incidences of cardiac and liver toxicity, owing to its alteration to the vaccination microenvironment between successive injections. Our strategy highlights the importance of fine-tuning adjuvant effect dynamics in optimizing mRNA vaccines for clinical application.

Author Info: (1) College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China. (2) College of Pharmaceutical Sciences, Zhejiang Universit

Author Info: (1) College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China. (2) College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China. (3) College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China. (4) College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China. (5) College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China. (6) College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China. (7) College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China. (8) Department of Ultrasound, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P. R. China. (9) Zhejiang Institute for Food and Drug Control, 325 Pingle Street, Hangzhou, Zhejiang 310004, P. R. China. (10) College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, 79 Qingchun Road, Shangcheng District, Hangzhou, Zhejiang 310006, P. R. China. The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310006, P. R. China. Jinhua Institute of Zhejiang University, 498 Yiwu Street, Jinhua, Zhejiang 321299, P. R. China.

Citation: ACS Nano 2024 Jul 16 Epub07/16/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39011561

Antibiotics are associated with worse outcomes in lung cancer patients treated with chemotherapy and immunotherapy

(1) Elkrief A (2) Mndez-Salazar EO (3) Maillou J (4) Vanderbilt CM (5) Gogia P (6) Desilets A (7) Messaoudene M (8) Kelly D (9) Ladanyi M (10) Hellmann MD (11) Zitvogel L (12) Rudin CM (13) Routy B (14) Derosa L (15) Schoenfeld AJ

NPJ precision oncology - Open Access

Anti-PD(L)-1 inhibition combined with platinum doublet chemotherapy (Chemo-IO) has become the most frequently used standard of care regimen in patients with non-small cell lung cancer (NSCLC). The negative impact of antibiotics on clinical outcomes prior to anti-PD(L)-1 inhibition monotherapy (IO) has been demonstrated in multiple studies, but the impact of antibiotic exposure prior to initiation of Chemo-IO is controversial. We assessed antibiotic exposures at two time windows: within 60_days prior to therapy (-60_d window) and within 60_days prior to therapy and 42_days after therapy (-60_+_42d window) in 2028 patients with advanced NSCLC treated with Chemo-IO and IO monotherapy focusing on objective response rate (ORR: rate of partial response and complete response), progression-free survival (PFS), and overall survival (OS). We also assessed impact of antibiotic exposure in an independent cohort of 53 patients. Univariable and multivariable analyses were conducted along with a meta-analysis from similar studies. For the -60_d window, in the Chemo-IO group (N_=_769), 183 (24%) patients received antibiotics. Antibiotic exposure was associated with worse ORR (27% vs 40%, p_=_0.001), shorter PFS (3.9_months vs. 5.9_months, hazard ratio [HR] 1.35, 95%CI 1.1,1.6, p_=_0.0012), as well as shorter OS (10_months vs. 15_months, HR 1.50, 95%CI 1.2,1.8, p_=_0.00014). After adjusting for known prognostic factors in NSCLC, antibiotic exposure was independently associated with worse PFS (HR 1.39, 95%CI 1.35,1.7, p_=_0.002) and OS (HR 1.61, 95%CI 1.28,2.03, p_<_0.001). Similar results were obtained in the -60_+_42d window, and also in an independent cohort. In a meta-analysis of patients with NSCLC treated with Chemo-IO (N_=_4) or IO monotherapy (N_=_13 studies) antibiotic exposure before treatment was associated with worse OS among all patients (n_=_11,351) (HR 1.93, 95% CI 1.52, 2.45) and Chemo-IO-treated patients (n_=_1201) (HR 1.54, 95% CI 1.28, 1.84). Thus, antibiotics exposure prior to Chemo-IO is common and associated with worse outcomes, even after adjusting for other factors. These results highlight the need to implement antibiotic stewardship in routine oncology practice.

Author Info: (1) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. arielle.elkrief@umontreal.ca. Human Oncology and Pathogenesis Program, Memorial Sloan Ketter

Author Info: (1) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. arielle.elkrief@umontreal.ca. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. arielle.elkrief@umontreal.ca. Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. arielle.elkrief@umontreal.ca. University of Montreal Research Center (CR-CHUM), Montreal, QC, Canada. arielle.elkrief@umontreal.ca. Department of Hematology-Oncology, Centre Hospitalier de l'Universit de Montral (CHUM), Montreal, QC, Canada. arielle.elkrief@umontreal.ca. (2) University of Montreal Research Center (CR-CHUM), Montreal, QC, Canada. (3) University of Montreal Research Center (CR-CHUM), Montreal, QC, Canada. (4) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Department of Hematology-Oncology, Centre Hospitalier de l'Universit de Montral (CHUM), Montreal, QC, Canada. (7) University of Montreal Research Center (CR-CHUM), Montreal, QC, Canada. (8) Informatics Systems, Memorial Sloan Kettering Cancer, New York, NY, USA. (9) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Medicine, Weill Cornell Medical College, New York, NY, USA. (11) INSERM U1015, Gustave Roussy Cancer Campus, Universit Paris-Saclay, Villejuif, France. (12) Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Medicine, Weill Cornell Medical College, New York, NY, USA. (13) University of Montreal Research Center (CR-CHUM), Montreal, QC, Canada. Department of Hematology-Oncology, Centre Hospitalier de l'Universit de Montral (CHUM), Montreal, QC, Canada. (14) INSERM U1015, Gustave Roussy Cancer Campus, Universit Paris-Saclay, Villejuif, France. (15) Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. schoenfa@mskcc.org. Department of Medicine, Weill Cornell Medical College, New York, NY, USA. schoenfa@mskcc.org.

Citation: NPJ Precis Oncol 2024 Jul 16 8:143 Epub07/16/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39014160

Calibrated CAR Signaling Enables Low-Dose Therapy in Large B-Cell Lymphoma

(1) Park J (2) Palomba ML (3) Perica K (4) Devlin S (5) Shah G (6) Dahi P (7) Lin R (8) Salles G (9) Scordo M (10) Nath K (11) Valtis Y (12) Lynch A (13) Cathcart E (14) Zhang H (15) Schder H (16) Leithner D (17) Liotta K (18) Yu A (19) Stocker K (20) Li J (21) Dey A (22) Sellner L (23) Singh R (24) Sundaresan V (25) Zhao F (26) Mansilla-Soto J (27) He C (28) Meyerson J (29) Hosszu K (30) McAvoy D (31) Wang X (32) Riviere I (33) Sadelain M

Research square - Open Access | Free PMC Article

We designed a CD19-targeted CAR comprising a calibrated signaling module, termed 1XX, that differs from that of conventional CD28/CD3z and 4-1BB/CD3z CARs. Here we report the first-in-human, phase 1 clinical trial of 19(T2)28z-1XX CAR T cells in relapsed/refractory large B-cell lymphoma. We hypothesized that 1XX CAR T cells may be effective at low doses and investigated 4 doubling dose levels starting from 25x10 (6) CAR T cells. The overall response rate (ORR) was 82% and complete response (CR) rate 71% in the entire cohort (n=28) and 88% ORR and 75% CR in 16 patients treated at 25x10 (6) . With the median follow-up of 24 months, the 1-year EFS was 61% (95% CI: 45-82%). Overall, grade ³3 CRS and ICANS rates were low at 4% and 7%. The calibrated potency of the 1XX CAR affords excellent efficacy at low cell doses and may benefit the treatment of other hematological malignancies, solid tumors and autoimmunity.

Author Info: (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) (30) (31) (32) (33)

Citation: Res Sq 2024 Jul 2 Epub07/02/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39011120

Adeno-associated virus delivered CXCL9 sensitizes glioblastoma to anti-PD-1 immune checkpoint blockade

(1) von Roemeling CA (2) Patel JA (3) Carpenter SL (4) Yegorov O (5) Yang C (6) Bhatia A (7) Doonan BP (8) Russell R (9) Trivedi VS (10) Klippel K (11) Ryu DH (12) Grippin A (13) Futch HS (14) Ran Y (15) Hoang-Minh LB (16) Weidert FL (17) Golde TE (18) Mitchell DA

Nature communications - Open Access | Free PMC Article

There are numerous mechanisms by which glioblastoma cells evade immunological detection, underscoring the need for strategic combinatorial treatments to achieve appreciable therapeutic effects. However, developing combination therapies is difficult due to dose-limiting toxicities, blood-brain-barrier, and suppressive tumor microenvironment. Glioblastoma is notoriously devoid of lymphocytes driven in part by a paucity of lymphocyte trafficking factors necessary to prompt their recruitment and activation. Herein, we develop a recombinant adeno-associated virus (AAV) gene therapy that enables focal and stable reconstitution of the tumor microenvironment with C-X-C motif ligand 9 (CXCL9), a powerful call-and-receive chemokine for lymphocytes. By manipulating local chemokine directional guidance, AAV-CXCL9 increases tumor infiltration by cytotoxic lymphocytes, sensitizing glioblastoma to anti-PD-1 immune checkpoint blockade in female preclinical tumor models. These effects are accompanied by immunologic signatures evocative of an inflamed tumor microenvironment. These findings support AAV gene therapy as an adjuvant for reconditioning glioblastoma immunogenicity given its safety profile, tropism, modularity, and off-the-shelf capability.

Author Info: (1) Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA. christina.vonroemeling@neurosurgery.ufl.edu. Preston A. Wells, Jr. Center for Brain Tu

Author Info: (1) Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA. christina.vonroemeling@neurosurgery.ufl.edu. Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA. christina.vonroemeling@neurosurgery.ufl.edu. (2) Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA. Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA. (3) Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA. Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA. (4) Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA. Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA. (5) Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA. Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA. (6) Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA. Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA. (7) Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA. Department of Medicine, Hematology and Oncology, University of Florida, Gainesville, FL, USA. (8) Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA. Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA. (9) Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA. Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA. (10) Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA. Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA. (11) Goizueta Brain Health Institute, Emory University School of Medicine, Atlanta, GA, USA. (12) Department of Radiation Oncology, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA. (13) Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA. (14) Goizueta Brain Health Institute, Emory University School of Medicine, Atlanta, GA, USA. (15) Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA. Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA. (16) Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA. Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA. (17) Goizueta Brain Health Institute, Emory University School of Medicine, Atlanta, GA, USA. (18) Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA. duane.mitchell@neurosurgery.ufl.edu. Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA. duane.mitchell@neurosurgery.ufl.edu.

Citation: Nat Commun 2024 Jul 12 15:5871 Epub07/12/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38997283

Dendritic cells steering antigen and leukocyte traffic in lymph nodes

(1) Dotta E (2) Maciola AK (3) Baccega T (4) Pasqual G

FEBS letters

(1) Dotta E (2) Maciola AK (3) Baccega T (4) Pasqual G

FEBS letters

Dendritic cells (DCs) play a central role in initiating and shaping the adaptive immune response, thanks to their ability to uptake antigens and present them to T cells. Once in the lymph node (LN), DCs can spread the antigen to other DCs, expanding the pool of cells capable of activating specific T-cell clones. Additionally, DCs can modulate the dynamics of other immune cells, by increasing nave T-cell dwell time, thereby facilitating the scanning for cognate antigens, and by selectively recruiting other leukocytes. Here we discuss the role of DCs in orchestrating antigen and leukocyte trafficking within the LN, together with the implications of this trafficking on T-cell activation and commitment to effector function.

Author Info: (1) Laboratory of Synthetic Immunology, Oncology and Immunology Section, Department of Surgery Oncology and Gastroenterology, University of Padua, Italy. (2) Laboratory of Syntheti

Author Info: (1) Laboratory of Synthetic Immunology, Oncology and Immunology Section, Department of Surgery Oncology and Gastroenterology, University of Padua, Italy. (2) Laboratory of Synthetic Immunology, Oncology and Immunology Section, Department of Surgery Oncology and Gastroenterology, University of Padua, Italy. (3) Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. (4) Laboratory of Synthetic Immunology, Oncology and Immunology Section, Department of Surgery Oncology and Gastroenterology, University of Padua, Italy. Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.

Citation: FEBS Lett 2024 Jul 12 Epub07/12/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38997244

Neoadjuvant and adjuvant pembrolizumab in advanced high-grade serous carcinoma: the randomized phase II NeoPembrOV clinical trial

(1) Ray-Coquard IL (2) Savoye AM (3) Schiffler C (4) Mouret-Reynier MA (5) Derbel O (6) Kalbacher E (7) LeHeurteur M (8) Martinez A (9) Cornila C (10) Martinez M (11) Bengrine Lefevre L (12) Priou F (13) Cloarec N (14) Venat L (15) Selle F (16) Berton D (17) Collard O (18) Coquan E (19) Le Saux O (20) Treilleux I (21) Gouerant S (22) Angelergues A (23) Joly F (24) Tredan O

Nature communications - Open Access

This open-label, non-comparative, 2:1 randomized, phase II trial (NCT03275506) in women with stage IIIC/IV high-grade serous carcinoma (HGSC) for whom upfront complete resection was unachievable assessed whether adding pembrolizumab (200_mg every 3 weeks) to standard-of-care carboplatin plus paclitaxel yielded a complete resection rate (CRR) of at least 50%. Postoperatively patients continued assigned treatment for a maximum of 2 years. Postoperative bevacizumab was optional. The primary endpoint was independently assessed CRR at interval debulking surgery. Secondary endpoints were Completeness of Cytoreduction Index (CCI) and peritoneal cancer index (PCI) scores, objective and best response rates, progression-free survival, overall survival, safety, postoperative morbidity, and pathological complete response. The CRR in 61 pembrolizumab-treated patients was 74% (one-sided 95% CI_=_63%), exceeding the prespecified ³50% threshold and meeting the primary objective. The CRR without pembrolizumab was 70% (one-sided 95% CI_=_54%). In the remaining patients CCI scores were ³3 in 27% of the standard-of-care group and 18% of the investigational group and CC1 in 3% of the investigational group. PCI score decreased by a mean of 9.6 in the standard-of-care group and 10.2 in the investigational group. Objective response rates were 60% and 72%, respectively, and best overall response rates were 83% and 90%, respectively. Progression-free survival was similar with the two regimens (median 20.8 versus 19.4 months in the standard-of-care versus investigational arms, respectively) but overall survival favored pembrolizumab-containing therapy (median 35.3 versus 49.8 months, respectively). The most common grade ³3 adverse events with pembrolizumab-containing therapy were anemia during neoadjuvant therapy and infection/fever postoperatively. Pembrolizumab was discontinued prematurely because of adverse events in 23% of pembrolizumab-treated patients. Combining pembrolizumab with neoadjuvant chemotherapy is feasible for HGSC considered not completely resectable; observed activity in some subgroups justifies further evaluation to improve understanding of the role of immunotherapy in HGSC.

Author Info: (1) Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) and Centre Lon Brard, University Claude Bernard, Lyon, France. isabelle.ray-coquard@lyon.unicance

Author Info: (1) Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) and Centre Lon Brard, University Claude Bernard, Lyon, France. isabelle.ray-coquard@lyon.unicancer.fr. (2) GINECO and Institut Jean Godinot, Reims, France. (3) Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) and Centre Lon Brard, University Claude Bernard, Lyon, France. (4) GINECO and Department of Medical Oncology, Centre Jean Perrin, Clermont-Ferrand, France. (5) GINECO and Institut de Cancrologie, Hpital Priv Jean Mermoz, Lyon, France. (6) GINECO and Centre Hospitalier Universitaire Jean Minjoz, Besanon, France. (7) GINECO and Medical Oncology Department, Centre Henri-Becquerel, Rouen, France. (8) GINECO and Institut Claudius Rgaud, Institut Universitaire du Cancer de Toulouse (IUCT) Oncopole, Toulouse, France. (9) GINECO and Centre Hospitalier Rgional d'Orlans, Orleans, France. (10) GINECO and Clinique Pasteur, Toulouse, France. (11) GINECO and Centre Georges-Franois Leclerc, Dijon, France. (12) GINECO and Centre Hospitalier Dpartemental Vende, La Roche-Sur-Yon, France. (13) GINECO and Centre Hospitalier Henri Duffaut d'Avignon, Avignon, France. (14) GINECO and Centre Hospitalier Universitaire Dupuytren, Limoges, France. (15) GINECO and Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris, France. (16) GINECO and Institut de Cancrologie de l'Ouest, Centre Ren Gauducheau, Saint-Herblain, France. (17) GINECO and Institut de Cancrologie de la Loire, Saint-Priest-en-Jarez, France. Center of Medical Oncology, Hpital Priv de la Loire, Saint-Etienne, France. (18) GINECO and Department of Medical Oncology, Centre Franois Baclesse, University Caen Normandie, Caen, France. (19) Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) and Centre Lon Brard, University Claude Bernard, Lyon, France. Cancer Research Center of Lyon (CRCL), UMR INSERM 1052, Centre Lon Brard, CNRS 5286, Lyon, France. (20) Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO) and Centre Lon Brard, University Claude Bernard, Lyon, France. (21) GINECO and Medical Oncology Department, Centre Henri-Becquerel, Rouen, France. (22) GINECO and Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris, France. (23) GINECO and Department of Medical Oncology, Centre Franois Baclesse, University Caen Normandie, Caen, France. (24) GINECO and Department of Medical Oncology, Centre Lon Brard, Lyon, France.

Citation: Nat Commun 2024 Jul 16 15:5931 Epub07/16/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39013870

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CX3CL1 release during immunogenic apoptosis is associated with enhanced anti-tumour immunity

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Robust anti-tumor immunity through the integration of targeted lipid nanoparticle-based mRNA nanovaccines with PD-1/PD-L1 blockade

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Beyond Cytotoxic Potency: Disposition Features Required to Design ADC Payload

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Crosstalk between Circadian Rhythm Dysregulation and Tumorigenesis, Tumor Metabolism and Tumor Immune Response

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Chronological Management of Adjuvant Effect for Optimized mRNA Vaccine Inspired by Natural Virus Infection

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Calibrated CAR Signaling Enables Low-Dose Therapy in Large B-Cell Lymphoma

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Adeno-associated virus delivered CXCL9 sensitizes glioblastoma to anti-PD-1 immune checkpoint blockade

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Neoadjuvant and adjuvant pembrolizumab in advanced high-grade serous carcinoma: the randomized phase II NeoPembrOV clinical trial

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