ACIR Journal Articles

Anti-CTLA-4 generates greater memory response than anti-PD-1 via TCF-1 Featured

(1) Mok S (2) Liu H (3) Agaç Çobanoglu D (4) Anang NAS (5) Mancuso JJ (6) Wherry EJ (7) Allison JP

Proceedings of the National Academy of Sciences of the United States of America - Open Access | Free PMC Article

Mok et al. investigated the durability of immunity induced by either anti-CTLA-4 or anti-PD-1, and found that memory T cells generated by anti-CTLA-4 exhibited greater expansion, cytokine production, and antitumor activity than those generated by anti-PD-1. Anti-CTLA-4 was found to preserve more TCF-1⁺ T cells during priming, while anti-PD-1 supported more TOX⁺ cells. In mice, conditional knockout of Tcf7 in CD8⁺ T cells impaired memory induced by anti-CTLA-4, but not anti-PD-1, while conditional knockout of Tox in CD8⁺ T cells showed no impact on the formation of memory in either therapy. The memory responses induced by anti-CTLA-4 were also strongly supported by CD4⁺ T cells, while the effects in anti-PD-1 were not.

(1) Mok S (2) Liu H (3) Agaç Çobanoglu D (4) Anang NAS (5) Mancuso JJ (6) Wherry EJ (7) Allison JP

Proceedings of the National Academy of Sciences of the United States of America - Open Access | Free PMC Article

ABSTRACT: The effects of T cell differentiation arising from immune checkpoint inhibition targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on the immunological memory response remain unclear. Our investigation into the effects of anti-CTLA-4 and anti-PD-1 on memory T cell formation in mice reveals that memory T cells generated by anti-CTLA-4 exhibit greater expansion, cytokine production, and antitumor activity than those from anti-PD-1. Notably, anti-CTLA-4 preserves more T cell factor-1 (TCF-1)+ T cells during priming, while anti-PD-1 leads to more thymocyte selection-associated high mobility group box (TOX)+ T cells. Experiments using conditional Tcf7- or Tox-knockout mice highlight that TCF-1 is essential for the memory response generated by anti-CTLA-4, whereas TOX deletion alone in T cells has no effect on the response to anti-PD-1. Deepening our understanding of how checkpoint inhibition affects memory response is crucial for advancing our understanding of the enduring impacts of these immunotherapies on the immune system.

Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (2) Department of Immunology, The University of Texas MD Anderson Cancer Center,

Author Info: (1) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (2) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (3) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (4) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (5) James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. (6) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104. (7) Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX 77030. Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.

Citation: Proc Natl Acad Sci U S A 2025 Jan 14 122:e2418985122 Epub01/09/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39786926

Molecular dynamics at immune synapse lipid rafts influence the cytolytic behavior of CAR T cells Spotlight

(1) Gad AZ (2) Morris JS (3) Godret-Miertschin L (4) Montalvo MJ (5) Kerr SS (6) Berger H (7) Lee JCH (8) Saadeldin AM (9) Abu-Arja MH (10) Xu S (11) Vasileiou S (12) Brock RM (13) Fousek K (14) Sheha MF (15) Srinivasan M (16) Li Y (17) Saeedi A (18) R Levental K (19) Leen AM (20) Mamonkin M (21) Carisey A (22) Varadarajan N (23) Hegde M (24) Joseph SK (25) Levental I (26) Mukherjee M (27) Ahmed N

Science advances - Open Access | Free PMC Article

To relate clinical outcomes to molecular-level differences between CD28 and 4-1BB CAR T cells, Gad et al. investigated the CAR immune synapse (CARIS). Compared to 4-1BB CARs, CD28 CARs associated with membrane lipid rafts and clustered at the CARIS more rapidly upon target encounter, resulting in stronger lytic granule polarization, shorter contact time, faster cytotoxicity, enhanced serial killing, and effector CD8⁺ bias. 4-1BB CAR T cells were more proliferative, had higher adhesion molecule (LFA-1, ICAM-1) expression, maintained stronger attachments to target cells, and killed (more slowly) via FasL.

Contributed by Alex Najibi

Science advances - Open Access | Free PMC Article

ABSTRACT: Chimeric antigen receptor T cells (CART) targeting CD19 through CD28.ζ signaling induce rapid lysis of leukemic blasts, contrasting with persistent tumor control exhibited by 4-1BB.ζ-CART. We reasoned that molecular dynamics at the CART immune synapse (CARIS) could explain differences in their tumor rejection kinetics. We observed that CD28.ζ-CART engaged in brief highly lethal CARIS and mastered serial killing, whereas 4-1BB.ζ-CART formed lengthy CARIS and relied on robust expansion and cooperative killing. We analyzed CARIS membrane lipid rafts (mLRs) and found that, upon tumor engagement, CD28.ζ-CAR molecules rapidly but transiently translocated into mLRs, mobilizing the microtubular organizing center and lytic granules to the CARIS. This enabled fast CART recovery and sensitivity to low target site density. In contrast, gradual accumulation of 4-1BB.ζ-CAR and LFA-1 molecules at mLRs built mechanically tonic CARIS mediating chronic Fas ligand-based killing. The differences in CD28.ζ- and 4-1BB.ζ-CARIS dynamics explain the distinct cytolytic behavior of CART and can guide engineering of more adaptive effective cellular products.

Author Info: (1) Interdepartmental Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA. Texas Children's Cancer Center, Texas Child

Author Info: (1) Interdepartmental Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA. Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (2) Interdepartmental Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA. Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (3) Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (4) William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA. (5) Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Immunology & Microbiology Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA. (6) Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (7) Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Texas Children's Hospital William T. Shearer Center for Human Immunobiology, Houston, TX 77030, USA. (8) Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Development, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA. (9) Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (10) Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (11) Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (12) Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (13) Interdepartmental Translational Biology and Molecular Medicine Graduate Program, Baylor College of Medicine, Houston, TX 77030, USA. Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (14) Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (15) Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (16) William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA. (17) William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA. (18) Department of Molecular Physiology and Biological Physics, Center for Molecular and Cell Physiology, University of Virginia, Charlottesville, VA 22903, USA. (19) Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (20) Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA. (21) Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Texas Children's Hospital William T. Shearer Center for Human Immunobiology, Houston, TX 77030, USA. (22) William A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, TX 77204, USA. (23) Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (24) Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. (25) Department of Molecular Physiology and Biological Physics, Center for Molecular and Cell Physiology, University of Virginia, Charlottesville, VA 22903, USA. (26) Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Texas Children's Hospital William T. Shearer Center for Human Immunobiology, Houston, TX 77030, USA. (27) Texas Children's Cancer Center, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Center for Cell and Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.

Citation: Sci Adv 2025 Jan 10 11:eadq8114 Epub01/10/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39792660

Increased functional potency of multi-edited CAR-T cells manufactured by a non-viral transfection system

(1) O'Sullivan A (2) Case S (3) McCrudden A (4) Hackett E (5) Gallagher L (6) Martin D (7) Johnson GP (8) Mahadik K (9) Kienzle T (10) Lim JK (11) Nashat A (12) Srinivasan K (13) Lowdell MW (14) O'Flynn L (15) Frankish J

Molecular therapy. Methods & clinical development - Open Access | Free PMC Article

Chimeric antigen receptor (CAR)-T cell therapy represents a breakthrough for the treatment of hematological malignancies. However, to treat solid tumors and certain hematologic cancers, next-generation CAR-T cells require further genetic modifications to overcome some of the current limitations. Improving manufacturing processes to preserve cell health and function of edited T cells is equally critical. Here, we report that Solupore, a Good Manufacturing Practice-aligned, non-viral physicochemical transfection system, can be used to manufacture multi-edited CAR-T cells using CRISPR-Cas9 ribonucleoproteins while maintaining robust cell functionality. When compared to electroporation, an industry standard, T cells that were triple edited using Solupore had reduced levels of apoptosis and maintained similar proportions of stem cell memory T cells with higher oxidative phosphorylation levels. Following lentiviral transduction with a CD19 CAR, and subsequent cryopreservation, triple-edited CAR-T cells manufactured using Solupore demonstrated improved immunological synapse strength to target CD19(+) Raji cells and enhanced cellular cytotoxicity compared with electroporated CAR-T cells. In an in vivo mouse model (NSG), Solupore triple-edited CAR-T cells enhanced tumor growth inhibition by more than 30-fold compared to electroporated cells.

Author Info: (1) Avectas, Cherrywood Business Park, Dublin, Ireland. (2) Avectas, Cherrywood Business Park, Dublin, Ireland. (3) Avectas, Cherrywood Business Park, Dublin, Ireland. (4) Avectas,

Author Info: (1) Avectas, Cherrywood Business Park, Dublin, Ireland. (2) Avectas, Cherrywood Business Park, Dublin, Ireland. (3) Avectas, Cherrywood Business Park, Dublin, Ireland. (4) Avectas, Cherrywood Business Park, Dublin, Ireland. (5) Avectas, Cherrywood Business Park, Dublin, Ireland. (6) Avectas, Cherrywood Business Park, Dublin, Ireland. (7) Avectas, Cherrywood Business Park, Dublin, Ireland. (8) Avectas, Cherrywood Business Park, Dublin, Ireland. (9) Avectas, Cherrywood Business Park, Dublin, Ireland. (10) Avectas, Cherrywood Business Park, Dublin, Ireland. (11) Avectas, Cherrywood Business Park, Dublin, Ireland. (12) Avectas, Cherrywood Business Park, Dublin, Ireland. (13) University College London, Cancer Institute, London, UK. (14) Avectas, Cherrywood Business Park, Dublin, Ireland. (15) Avectas, Cherrywood Business Park, Dublin, Ireland.

Citation: Mol Ther Methods Clin Dev 2025 Mar 13 33:101389 Epub12/05/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39811687

A non-randomised open-label exploratory 'window of opportunity' study of TG02 treatment in patients with locally advanced primary and recurrent RAS mutant colorectal cancer

(1) Roth S (2) Wilson KC (3) Ramsay RG (4) Mitchell C (5) Sampurno S (6) Pham TD (7) Huei Kong JC (8) Wong SQ (9) Heriot AG (10) Deva S (11) Burge M (12) Sverdrup C (13) Moller AS (14) Kuryk L (15) Eriksen JA (16) Jaderberg M (17) Zalcberg JR (18) Michael M

Heliyon - Open Access | Free PMC Article

BACKGROUND: TG02 is a peptide-based cancer vaccine eliciting immune responses to oncogenic codon 12/13 RAS mutations. This phase 1 clinical trial (NCT02933944) assessed the safety and immunological efficacy of TG02 adjuvanted by GM-CSF in patients with KRAS-mutant colorectal cancer. METHODS: In the interval between completing CRT and pelvic exenteration, patients with resectable KRAS mutation-positive, locally advanced primary or current colorectal cancer, received 5-6 doses of TG02/GM-CSF. Immune response was defined as a positive delayed-type hypersensitivity or positive T cell proliferation assay response. Tumour biopsies were analysed for tumour-infiltrating lymphocytes (TILs) and blood for CEA and ctDNA. TILs and tumouroids were cultured, characterised and tested for their killing efficacy. RESULTS: Six patients with rectal cancer were recruited to evaluate TG02. Three patients experienced a total of 16 treatment-related adverse events; all grade 1. Four of the 6 patients (66.7 %) had at least one vaccine-induced TG02 immune response. Flow cytometry analysis showed high proportion of PD-1-expressing TILs in 2 of 3 patient specimens' post-treatment. A partial to near complete pathological response was reported in 4 of 6 patients. CONCLUSIONS: This study demonstrated that TG02/GM-CSF was well tolerated and induced a vaccine specific systemic immune response in the majority of patients. Low numbers limit conclusive clinical outcome reporting. High PD-1 expression on post-treatment TILs encourages the addition of an immune checkpoint inhibitor to TG02 and potentially other studies of peptide vaccines in future studies.

Author Info: (1) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia. Monash Uni

Author Info: (1) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia. Monash University Department of Surgery, Alfred Hospital, Melbourne, Australia. (2) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia. Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia. (3) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia. (4) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia. Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia. (5) Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia. (6) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia. Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia. (7) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia. Monash University Department of Surgery, Alfred Hospital, Melbourne, Australia. Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia. (8) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia. Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Australia. (9) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia. Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia. (10) Department of Medical Oncology, Auckland City Hospital, Auckland, New Zealand. (11) Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, Australia. University of Queensland, St Lucia, Brisbane, Australia. (12) Targovax ASA, Oslo, Norway. (13) Targovax ASA, Oslo, Norway. (14) Targovax ASA, Oslo, Norway. (15) Targovax ASA, Oslo, Norway. (16) Targovax ASA, Oslo, Norway. (17) Department of Medical Oncology, Alfred Health & School of Public Health, Faculty of Medicine, Monash University, Melbourne, Australia. (18) Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.

Citation: Heliyon 2025 Jan 15 11:e41364 Epub12/19/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39811281

Potential and development of cellular vesicle vaccines in cancer immunotherapy

(1) Zhao W (2) Li X (3) Guan J (4) Yan S (5) Teng L (6) Sun X (7) Dong Y (8) Wang H (9) Tao W

Discover oncology - Open Access

(1) Zhao W (2) Li X (3) Guan J (4) Yan S (5) Teng L (6) Sun X (7) Dong Y (8) Wang H (9) Tao W

Discover oncology - Open Access

Cancer vaccines are promising as an effective means of stimulating the immune system to clear tumors as well as to establish immune surveillance. In this paper, we discuss the main platforms and current status of cancer vaccines and propose a new cancer vaccine platform, the cytosolic vesicle vaccine. This vaccine has a unique structure that can integrate antigen and adjuvant carriers to improve the delivery efficiency and immune activation ability, which brings new ideas for cancer vaccine design. Tumor exosomes carry antigens and MHC-peptide complexes, which can provide tumor antigens to antigen-processing cells and increase the chances of recognition of tumor antigens by immune cells. DEVs play a role in amplifying the immune response by acting as carriers for the dissemination of antigenic substances in dendritic cells. OMVs, with their natural adjuvant properties, are one of the advantages for the preparation of antitumor vaccines. This paper presents the advantages of these three bacteria/extracellular vesicles as cancer vaccines and discusses the potential applications of functionally modified extracellular vesicles as cancer vaccines after cellular engineering or genetic engineering, as well as current clinical trials of extracellular vesicle vaccines. In summary, extracellular vesicle vaccines are a promising direction for cancer vaccine research.

Author Info: (1) Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, China. (2) Department of Br

Author Info: (1) Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, China. (2) Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, China. Department of Breast Surgery, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150081, China. (3) Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, China. (4) Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, China. (5) Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, China. (6) Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, China. (7) Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, China. (8) Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, China. (9) Department of Breast Surgery, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, 150001, China. twy0116@126.com. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China. twy0116@126.com.

Citation: Discov Oncol 2025 Jan 15 16:48 Epub01/15/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39812959

Exploring the role of adipokines in exercise-induced inhibition of tumor growth

(1) Qian Y (2) Bu Z (3) Qin Y (4) Qian S (5) Qin L (6) Zhou S (7) Wang Q (8) Xian L (9) Hu L (10) Xiong Y (11) Zhang Y (12) Wang C

Sports medicine and health science - Open Access | Free PMC Article

(1) Qian Y (2) Bu Z (3) Qin Y (4) Qian S (5) Qin L (6) Zhou S (7) Wang Q (8) Xian L (9) Hu L (10) Xiong Y (11) Zhang Y (12) Wang C

Sports medicine and health science - Open Access | Free PMC Article

The integration of exercise prescriptions into cancer adjuvant therapy presents challenges stemming from the ambiguity surrounding the precise mechanism through which exercise intervention mitigates the risk of hepatocellular carcinoma (HCC) mortality and recurrence. Elucidation of this specific mechanism has substantial social and clinical implications. In this study, tumor-bearing mice engaged in voluntary wheel running exhibited a notable decrease in tumor growth, exceeding 30%. Microarray analysis revealed an upregulation of cytokine-related pathways as a potential explanation for this effect. The inclusion of granulocyte-macrophage colony-stimulating factor (GM-CSF) was found to enhance tumor cell proliferation, while the absence of GM-CSF resulted in a marked inhibition of tumor cell growth. The findings suggest that exercise-induced serum from mice can impede the proliferation of mouse tumor cells, with the adipokine chemerin inhibiting the growth factor GM-CSF. Additionally, exercise was found to stimulate chemerin secretion by brown adipose tissue. Chemerin suppression led to a reduction in the inhibition of tumor cell proliferation. The results of this study suggest that exercise may stimulate the release of adipokines from brown adipose tissue, transport them through the blood to the distant tumor microenvironment, and downregulate GM-CSF expression, alleviating tumor immunosuppression in the tumor microenvironment, thereby inhibiting at HCC progression. These findings provide a theoretical basis for incorporating exercise prescription into cancer treatment.

Author Info: (1) School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China. (2) School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China. (3) School o

Author Info: (1) School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China. (2) School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China. (3) School of Basic Medicine and Forensic Medicine, Sichuan University, Chengdu, China. (4) West China School of Public Health, Sichuan University, Chengdu, China. (5) School of Basic Medicine and Forensic Medicine, Sichuan University, Chengdu, China. (6) School of Basic Medicine and Forensic Medicine, Sichuan University, Chengdu, China. (7) School of Basic Medicine and Forensic Medicine, Sichuan University, Chengdu, China. (8) School of Basic Medicine and Forensic Medicine, Sichuan University, Chengdu, China. (9) School of Basic Medicine and Forensic Medicine, Sichuan University, Chengdu, China. (10) School of Basic Medicine and Forensic Medicine, Sichuan University, Chengdu, China. (11) School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China. (12) School of Sports Medicine and Health, Chengdu Sport University, Chengdu, China.

Citation: Sports Med Health Sci 2025 Mar 7:143-156 Epub03/21/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39811408

Donor-derived GD2-specific CAR T cells in relapsed or refractory neuroblastoma

(1) Quintarelli C (2) Del Bufalo F (3) De Ioris MA (4) Guercio M (5) Algeri M (6) Pagliara D (7) Silvestris DA (8) Di Nardo M (9) Sinibaldi M (10) Di Cecca S (11) Iaffaldano L (12) Manni S (13) Fustaino V (14) Garganese MC (15) Colafati GS (16) Bertaina V (17) Becilli M (18) Mastronuzzi A (19) Fabozzi F (20) Gunetti M (21) Iacovelli S (22) Bugianesi R (23) Macchia S (24) Li Pira G (25) Cefalo MG (26) Leone G (27) Del Baldo G (28) De Angelis B (29) Locatelli F

Nature medicine

Allogeneic chimeric antigen receptor (CAR) T cells targeting disialoganglioside-GD2 (ALLO_GD2-CART01) could be a therapeutic option for patients with relapsed or refractory, high-risk neuroblastoma (r/r HR-NB) whose tumors did not respond to autologous GD2-CART01 or who have profound lymphopenia. We present a case series of five children with HR-NB refractory to more than three different lines of therapy who received ALLO_GD2-CART01 in a hospital exemption setting. Four of them had previously received allogeneic hematopoietic stem cell transplantation. All patients experienced grade 2 or 3 cytokine release syndrome and one grade 2 neurotoxicity. Moderate acute graft-versus-host-disease occurred in four patients. ALLO_GD2-CART01 persisted for >6_weeks. Post-treatment, two complete responses were achieved and one maintained; in addition, one partial response and one stable disease were observed. Comparing the transcriptomic profiles obtained by RNA sequencing analyses of drug products with patient-matched, peripheral blood ALLO_GD2-CART01 collected at expansion, we found upregulation of genes associated with T cell activation and migration. In addition, after infusion, transcriptomic signaling analysis showed enrichment of genes involved in response to decreased oxygen levels, humoral immune response, cell polarization and immune-synapse formation. In comparison to autologous CAR T cells, ALLO_GD2-CAR T cells were characterized by pathways associated with T cell proliferation, immune-synapse formation and cell chemotaxis. The safety and efficacy of ALLO_GD2-CART01 in children with r/r HR-NB deserve further investigation in a prospective trial.

Author Info: (1) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Ita

Author Info: (1) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy. (2) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (3) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (4) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (5) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. Department of Health Sciences, Magna Graecia University, Catanzaro, Italy. (6) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (7) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (8) Pediatric Intensive Care Unit, IRCCS, Bambino Ges Children's Hospital, Rome, Italy. (9) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (10) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (11) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (12) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (13) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (14) Nuclear Medicine Unit/Imaging Department, IRCCS, Bambino Ges Children's Hospital, Rome, Italy. (15) Imaging Department, IRCCS, Bambino Ges Children's Hospital, Rome, Italy. (16) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (17) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (18) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (19) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (20) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (21) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (22) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (23) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (24) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (25) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (26) Transfusion Unit, Department of Laboratories, IRCCS, Bambino Ges Children's Hospital, Rome, Italy. (27) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (28) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. (29) Department of Hematology/Oncology, Cell and Gene Therapy, Scientific Institute for Research, Hospitalization and Healthcare (IRCCS), Bambino Ges Children's Hospital, Rome, Italy. franco.locatelli@opbg.net. Catholic University of the Sacred Heart, Department of Life Sciences and Public Health, Rome, Italy. franco.locatelli@opbg.net.

Citation: Nat Med 2025 Jan 15 Epub01/15/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39815015

Macrophage-specific in vivo RNA editing promotes phagocytosis and antitumor immunity in mice

(1) Chen Y (2) Chen X (3) Zhang Y (4) Wang M (5) Yang M (6) Wang R (7) Yan X (8) Shao S (9) Xin H (10) Hu Q (11) Wei W (12) Ping Y

Science translational medicine

(1) Chen Y (2) Chen X (3) Zhang Y (4) Wang M (5) Yang M (6) Wang R (7) Yan X (8) Shao S (9) Xin H (10) Hu Q (11) Wei W (12) Ping Y

Science translational medicine

Macrophages play a central role in antitumor immunity, making them an attractive target for gene therapy strategies. However, macrophages are difficult to transfect because of nucleic acid sensors that can trigger the degradation of foreign plasmid DNA. Here, we developed a macrophage-specific editing (MAGE) system by which compact plasmid DNA encoding a CasRx editor can be delivered to macrophages by a poly(_-amino ester) (PBAE) carrier to bypass the DNA sensor and enable RNA editing in vitro and in vivo. We identified a four-arm branched PBAE with 1-(2-aminoethyl)-4-methylpiperazine end-capping (PBAE29) that enables highly efficient macrophage transfection. PBAE29-mediated transfection of cultured macrophages stimulated less inflammatory cytokine production and inflammasome activation compared with traditional lipofectamine or electroporation-mediated plasmid delivery. Transfection efficiency was further improved by delivering CasRx by minicircle plasmid. The MAGE system incorporated a layer of carboxylated-mannan coating to target macrophage mannose receptors and a macrophage-specific promoter for enhanced selectivity. The delivery of CasRx with guide RNA targeting the transcripts for sialic acid-binding immunoglobulin similar to lectin 10 and signal regulatory protein alpha expression resulted in effective protein knockdown, improving macrophage phagocytosis. The MAGE system also showed efficacy in targeting macrophages in vivo, stimulating antitumor immune responses and reducing tumor volume in murine tumor models, including patient-derived pancreatic adenocarcinoma xenografts in humanized mice. In sum, the MAGE system presents a promising platform for in vivo macrophage-specific delivery of RNA editing tools that can be applied as a cancer therapy.

Author Info: (1) College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China. Liangzhu Laboratory, Zhejia

Author Info: (1) College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China. Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China. (2) College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China. Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China. Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (3) College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China. (4) Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (5) Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (6) College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China. (7) College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China. Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China. (8) Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (9) College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China. (10) Zhejiang Provincial Key Laboratory of Pancreatic Disease, MOE Joint International Research Laboratory of Pancreatic Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (11) State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China. School of Chemical Engineering, University of Chinese Academy of Sciences, Beijing 100049, China. (12) College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China. Liangzhu Laboratory, Zhejiang University, Hangzhou 311121, China.

Citation: Sci Transl Med 2025 Jan 15 17:eadl5800 Epub01/15/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39813319

Selinexor (KPT-330) in Combination with Immune Checkpoint Inhibition in Uveal Melanoma: A Phase 1B Trial

(1) Gouda MA (2) Zarifa A (3) Yang Y (4) Stephen B (5) Gurses SA (6) Sprenger A (7) Tian Y (8) Derbala MH (9) Oliva IG (10) Meric-Bernstam F (11) Patel SP

Journal of immunotherapy and precision oncology - Open Access | Free PMC Article

(1) Gouda MA (2) Zarifa A (3) Yang Y (4) Stephen B (5) Gurses SA (6) Sprenger A (7) Tian Y (8) Derbala MH (9) Oliva IG (10) Meric-Bernstam F (11) Patel SP

Journal of immunotherapy and precision oncology - Open Access | Free PMC Article

INTRODUCTION: Uveal melanoma remains a disease with aggressive behavior and poor prognosis despite advances in clinical management. Because monotherapy with immune checkpoint inhibitors has led to limited improvement in response rates, combination with other agents that act on the biological basis of oncogenesis has been proposed as a possible therapeutic strategy. METHODS: We designed a phase 1b trial to test the safety and tolerability of selinexor in combination with immune checkpoint inhibitors in patients with advanced uveal melanoma. Patients received selinexor 60 mg PO twice weekly with standard of care, commercially available immune checkpoint inhibitor of the investigator's choice. In one patient receiving nivolumab and ipilimumab as the immunotherapy backbone, selinexor 60 mg PO was given once weekly. RESULTS: We included 10 patients with uveal melanoma who received treatment with either selinexor plus pembrolizumab (n = 9) or selinexor plus nivolumab and ipilimumab (n = 1). The most common adverse events of any grade were neutropenia, thrombocytopenia, leukopenia, and anemia. Additional common nonhematological toxicities included hyponatremia, nausea, and vomiting. Dose reductions were required in six patients (60%). Among nine patients with evaluable disease, eight had stable disease as the best response. The median progression-free and overall survival were 6 months (95% CI: 4, not reached and 17 months (95% CI: 7, not reached), respectively. CONCLUSION: The combination of selinexor and immunotherapy was safe and showed a side effect profile consistent with previous reports. Clinical benefit was achieved in most patients and should be validated in larger phase 2 trials. ClinicalTrials.gov ID: NCT02419495.

Author Info: (1) Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Investigational Cancer Therapeutics, T

Author Info: (1) Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2) Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (10) Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Division of Medical Oncology, Department of Medicine, University of Colorado Cancer Center, Aurora, CO, USA.

Citation: J Immunother Precis Oncol 2025 Feb 8:82-88 Epub01/15/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39816915

Personalized Nanovaccine Based on STING-Activating Nanocarrier for Robust Cancer Immunotherapy

(1) Li Y (2) Dong Y (3) Shen D (4) Guo Y (5) Cao Y (6) Zhang K (7) Li X (8) Zhu R (9) Yi J (10) Yao X (11) Dang X (12) Li R (13) Zhang Z (14) Qin Z (15) Yang W

ACS nano

(1) Li Y (2) Dong Y (3) Shen D (4) Guo Y (5) Cao Y (6) Zhang K (7) Li X (8) Zhu R (9) Yi J (10) Yao X (11) Dang X (12) Li R (13) Zhang Z (14) Qin Z (15) Yang W

ACS nano

Tumor-specific T cells play a vital role in potent antitumor immunity. However, their efficacy is severely affected by the spatiotemporal orchestration of antigen-presentation as well as the innate immune response in dendritic cells (DCs). Herein, we develop a minimalist nanovaccine that exploits a dual immunofunctional polymeric nanoplatform (DIPNP) to encapsulate ovalbumin (OVA) via electrostatic interaction when the nanocarrier serves as both STING agonist and immune adjuvant in DCs. In vitro results reveal that the nanocarrier induces STING activation via facilitating interferon regulatory factor 3 phosphorylation by block poly 18-crown-6-yl methacrylate (P18C6MA) mediated K(+) perturbation cascade with endoplasmic reticulum stress, and stimulates DC maturation via the Toll-like receptor 4 activation by primary amine. In vivo studies indicate that the smart nanovaccine dramatically inhibits tumor growth with a long-term immune memory response in both the B16-OVA and EG7-OVA tumor models. After combination with programmed death ligand-1 antibody (aPD-L1), mice survival rate is notably prolonged. In addition, DIPNP forms a personalized nanovaccine after resected autologous primary tumor cell membranes decoration with a high antitumor activity in a homologous distant tumor model. The rational design provides inspiration for personalized nanovaccine construction via immunofunctional nanocarriers.

Author Info: (1) Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzh

Author Info: (1) Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China. (2) Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China. (3) Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China. (4) School of Pharmaceutical Sciences, Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou University, Zhengzhou, Henan 450001, China. (5) School of Pharmaceutical Sciences, Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou University, Zhengzhou, Henan 450001, China. (6) School of Pharmaceutical Sciences, Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou University, Zhengzhou, Henan 450001, China. (7) Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China. (8) School of Pharmaceutical Sciences, Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou University, Zhengzhou, Henan 450001, China. (9) Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China. (10) Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China. (11) Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China. (12) Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China. (13) School of Pharmaceutical Sciences, Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou University, Zhengzhou, Henan 450001, China. (14) Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China. (15) Medical Research Center, The First Affiliated Hospital of Zhengzhou University, The Center of Infection and Immunity, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China. School of Pharmaceutical Sciences, Henan Key Laboratory of Nanomedicine for Targeting Diagnosis and Treatment, Zhengzhou University, Zhengzhou, Henan 450001, China.

Citation: ACS Nano 2025 Jan 16 Epub01/16/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39817337

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Molecular dynamics at immune synapse lipid rafts influence the cytolytic behavior of CAR T cells Spotlight

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Increased functional potency of multi-edited CAR-T cells manufactured by a non-viral transfection system

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Potential and development of cellular vesicle vaccines in cancer immunotherapy

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Exploring the role of adipokines in exercise-induced inhibition of tumor growth

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Donor-derived GD2-specific CAR T cells in relapsed or refractory neuroblastoma

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Macrophage-specific in vivo RNA editing promotes phagocytosis and antitumor immunity in mice

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Selinexor (KPT-330) in Combination with Immune Checkpoint Inhibition in Uveal Melanoma: A Phase 1B Trial

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Personalized Nanovaccine Based on STING-Activating Nanocarrier for Robust Cancer Immunotherapy

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Anti-CTLA-4 generates greater memory response than anti-PD-1 via TCF-1 Featured

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Molecular dynamics at immune synapse lipid rafts influence the cytolytic behavior of CAR T cells Spotlight

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Increased functional potency of multi-edited CAR-T cells manufactured by a non-viral transfection system

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A non-randomised open-label exploratory 'window of opportunity' study of TG02 treatment in patients with locally advanced primary and recurrent RAS mutant colorectal cancer

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Potential and development of cellular vesicle vaccines in cancer immunotherapy

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Exploring the role of adipokines in exercise-induced inhibition of tumor growth

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Donor-derived GD2-specific CAR T cells in relapsed or refractory neuroblastoma

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Macrophage-specific in vivo RNA editing promotes phagocytosis and antitumor immunity in mice

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Selinexor (KPT-330) in Combination with Immune Checkpoint Inhibition in Uveal Melanoma: A Phase 1B Trial

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Personalized Nanovaccine Based on STING-Activating Nanocarrier for Robust Cancer Immunotherapy

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