Journal Articles

Developing a multimodal therapy for glioblastoma using oncolytic virus delivering CD19 and EGFRvIII antigens and bi-specific CARs

Spotlight 

(1) Li J (2) Chaurasiya S (3) Sun G (4) Cui Q (5) Ye P (6) Qin Y (7) Zhou T (8) Wang X (9) Fong Y (10) Maus MV (11) Shi Y

Nature communications

Li et al. engineered an oncolytic vaccinia virus that expressed truncated CD19 and EGFRvIII on GBM cells (OVDual) and a bispecific CD19/EGFRvIII CAR-T (BiCAR-T). BiCAR-T cells effectively targeted OVDual-infected GBM cells in vitro, and intratumoral OVDual plus BiCAR-T reduced tumor burden in the xenograft model of GBM. Oncolytic vaccinia virus encoding mIL-15 and mIL-21 (OVmIL15/21) further enhanced CAR expansion, persistence, and cytotoxicity. Human pluripotent stem cell-derived (off-the-shelf) BiCAR-NK cells combined with OVDual and OVmIL15/21 showed similar antigen-specific cytotoxicity and in vivo efficacy, limiting immune escape.

Contributed by Shishir Pant

(1) Li J (2) Chaurasiya S (3) Sun G (4) Cui Q (5) Ye P (6) Qin Y (7) Zhou T (8) Wang X (9) Fong Y (10) Maus MV (11) Shi Y

Nature communications

Li et al. engineered an oncolytic vaccinia virus that expressed truncated CD19 and EGFRvIII on GBM cells (OVDual) and a bispecific CD19/EGFRvIII CAR-T (BiCAR-T). BiCAR-T cells effectively targeted OVDual-infected GBM cells in vitro, and intratumoral OVDual plus BiCAR-T reduced tumor burden in the xenograft model of GBM. Oncolytic vaccinia virus encoding mIL-15 and mIL-21 (OVmIL15/21) further enhanced CAR expansion, persistence, and cytotoxicity. Human pluripotent stem cell-derived (off-the-shelf) BiCAR-NK cells combined with OVDual and OVmIL15/21 showed similar antigen-specific cytotoxicity and in vivo efficacy, limiting immune escape.

Contributed by Shishir Pant

ABSTRACT: Glioblastoma is the most aggressive primary brain tumor with no cure, largely because of tumor heterogeneity and immunosuppressive tumor microenvironment. Chimeric antigen receptor (CAR)-T cell therapy is highly effective in blood cancers but exhibits limited efficacy in glioblastoma due to heterogeneous tumor antigen expression, antigen loss and poor persistence of tumor-targeting immune cells in glioblastoma. Here we show a multimodal immunotherapy strategy that integrates engineered immune cells with oncolytic viruses to overcome these barriers. We have developed bispecific CAR-T and CAR-NK cells in combination with oncolytic virus that delivers two tumor antigens to glioblastoma cells for effective CAR targeting. Moreover, oncolytic virus armed with membrane-bound interleukin-15 and interleukin-21 enhances immune cell expansion/persistence and cytotoxic activity. This combined approach improves anti-tumor efficacy in vitro and in vivo by limiting immune escape and enhancing anti-tumor immunity. Together, these findings establish a promising platform for multimodal immunotherapy targeting glioblastoma and other solid tumors.

Author Info: (1) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (2) Department of Surgery, City of Hope, 1500 E. Duar

Author Info: (1) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (2) Department of Surgery, City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (3) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (4) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (5) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (6) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (7) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (8) Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (9) Department of Surgery, City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. (10) Cellular Immunotherapy Program Cancer Center, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. (11) Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, USA. yshi@coh.org.

Citation: Nat Commun 2026 Apr 9 Epub04/09/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41957020

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Persistent T cell activation and cytotoxicity against glioblastoma following single oncolytic virus treatment in a clinical trial Featured  

(1) Meylan M (2) Tian Y (3) Wu L (4) Ling AL (5) Kovarsky D (6) Barlow GL (7) Nguyen LD (8) Pyrdol J (9) Marx S (10) Westphal L (11) Michel J (12) Gonzalez Castro LN (13) Dumont S (14) Santos A (15) Tirosh I (16) Suvˆ ML (17) Chiocca EA (18) Wucherpfennig KW

Cell

Following clinical evidence that a single oncolytic virus treatment was associated with immune activation signatures, Meylen, Tiian, Wu, Ling, et al. analyzed tumor samples and found that pre-existing TILs expanded upon treatment, resulting in deep and persistent T cell activation against tumor cells. While viral remnants were restricted to necrotic regions, granzyme B+ CD8+ T cells embedded deeply into tumors, showed persistent activation, and were located in close proximity to apoptotic tumor cells. These T cell observations further and that this correlated with longer-progression-free and overall survival.

(1) Meylan M (2) Tian Y (3) Wu L (4) Ling AL (5) Kovarsky D (6) Barlow GL (7) Nguyen LD (8) Pyrdol J (9) Marx S (10) Westphal L (11) Michel J (12) Gonzalez Castro LN (13) Dumont S (14) Santos A (15) Tirosh I (16) Suvˆ ML (17) Chiocca EA (18) Wucherpfennig KW

Cell

Following clinical evidence that a single oncolytic virus treatment was associated with immune activation signatures, Meylen, Tiian, Wu, Ling, et al. analyzed tumor samples and found that pre-existing TILs expanded upon treatment, resulting in deep and persistent T cell activation against tumor cells. While viral remnants were restricted to necrotic regions, granzyme B+ CD8+ T cells embedded deeply into tumors, showed persistent activation, and were located in close proximity to apoptotic tumor cells. These T cell observations further and that this correlated with longer-progression-free and overall survival.

ABSTRACT: A recent first-in-human clinical trial demonstrated that survival in glioblastoma (GBM) patients following rQNestin34.5v.2 oncolytic virus treatment was associated with immune activation signatures. This study was registered at ClinicalTrials.gov (NCT03152318). Here, we provide in situ evidence of ongoing T cell-mediated cytotoxicity against tumor cells at late time points following single treatment, with deep and persistent T cell infiltration into tumor regions. Shorter distances between cleaved caspase-3(+) tumor cells and granzyme B(+) T cells were associated with longer progression-free survival following treatment. Pre-existing tumor-infiltrating T cells expanded locally upon treatment, correlating with longer overall patient survival. T cells with an early activation program closely interacted with tumor cells and were strongly enriched upon treatment. Viral remnants were restricted to necrotic regions, while T cells infiltrated deeply into live tumor regions. These data demonstrate that single oncolytic virus treatment can expand pre-existing T cell clones and trigger persistent T cell-mediated immunity against GBM.

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA. (2) Department o

Author Info: (1) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA. (2) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA. (3) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA. (4) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Neuroscience Institute and Cancer Institute, Mass General Brigham, Boston, MA, USA. (5) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (6) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA. (7) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (8) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (9) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA. (10) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. (11) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM), Heidelberg, Germany; German Cancer Research Center (DKFZ), JRG Hematology and Immune Engineering, Heidelberg, Germany. (12) Department of Pathology and Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. (13) Department of Pathology and Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. (14) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Neuroscience Institute and Cancer Institute, Mass General Brigham, Boston, MA, USA. (15) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. (16) Department of Pathology and Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: suva.mario@mgh.harvard.edu. (17) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Neuroscience Institute and Cancer Institute, Mass General Brigham, Boston, MA, USA. Electronic address: eachiocca@mgb.org. (18) Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Immunology, Harvard Medical School, Boston, MA, USA; Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: kai_wucherpfennig@dfci.harvard.edu.

Citation: Cell 2026 Feb 11 Epub02/11/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41679299

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CD73 blockade enhances antitumor efficacy of oHSV in solid tumors by increasing macrophage-mediated antigen presentation Spotlight 

(1) Murphy SA (2) Li J (3) Sahu U (4) Swanner J (5) Lewis CT (6) Anchang B (7) Cui Y (8) Chiocca EA (9) Kaur B

Journal for immunotherapy of cancer

Murphy et al. showed that oncolytic HSV (oHSV) therapy increased extracellular adenosine (eADO) receptor B gene expression in solid tumors, and that worse prognosis correlated with high expression of the gene for the ADO-generating enzyme CD73 and adenosine signaling gene signatures. In solid tumor models, the TME of CD73 KO mice showed increased macrophage-mediated antigen presentation and CD4+ T cell cross-talk, and oHSV-treated CD73 KO mice exhibited greater tumor control than treated WT mice. oHSV plus CD73 Ab blockade increased CD8+ TMEM and TEFF and CD4+ TMEM TILs, and enhanced efficacy and memory.

Contributed by Paula Hochman

(1) Murphy SA (2) Li J (3) Sahu U (4) Swanner J (5) Lewis CT (6) Anchang B (7) Cui Y (8) Chiocca EA (9) Kaur B

Journal for immunotherapy of cancer

Murphy et al. showed that oncolytic HSV (oHSV) therapy increased extracellular adenosine (eADO) receptor B gene expression in solid tumors, and that worse prognosis correlated with high expression of the gene for the ADO-generating enzyme CD73 and adenosine signaling gene signatures. In solid tumor models, the TME of CD73 KO mice showed increased macrophage-mediated antigen presentation and CD4+ T cell cross-talk, and oHSV-treated CD73 KO mice exhibited greater tumor control than treated WT mice. oHSV plus CD73 Ab blockade increased CD8+ TMEM and TEFF and CD4+ TMEM TILs, and enhanced efficacy and memory.

Contributed by Paula Hochman

BACKGROUND: Oncolytic herpes simplex virus (oHSV) therapy is a live virus-based immunotherapy that lyses tumor cells which release antigens and activate antitumor immunity. oHSV therapy has been shown to increase ATP production and release of extracellular ATP (eATP). In the extracellular tumor microenvironment, eATP functions as an immune-activating damage-associated molecular pattern but is hydrolyzed to extracellular adenosine (eADO), which can be immune-suppressive. eADO is generated by the sequential action of ectoenzymes CD39 and CD73 (NT5E). Here, we examined the role of immunosuppressive eADO signaling in regulating antitumor immune efficacy of oHSV. METHODS: We evaluated changes in eADO signaling in vitro and in patient specimens after virotherapy. A genetic CD73 knock-out mouse model and blocking antibodies were used to assess the impact of CD73 on virotherapy in two different solid tumor models. Single-cell RNA sequencing was employed to assess changes in immune cell infiltration and communication. Flow cytometric immunophenotyping and immunofluorescent imaging were utilized to confirm single-cell sequencing predicted changes in tumor microenvironment. RESULTS: Transcriptomic analysis of patient tumors pre-virotherapy and post-virotherapy with CAN-3110 revealed increased expression of the adenosine receptor gene ADORA2B after treatment. High NT5E gene expression, as well as gene signatures suggestive of adenosine signaling, correlated with a significantly worse prognosis for patients with solid tumors. Single-cell sequencing of immune cells recruited to tumor-bearing brain hemispheres in CD73 knockout mice revealed an increase in macrophage-mediated antigen presentation and CD4(+) T cell cross-communication. Intracranial tumor-bearing CD73 knock-out mice treated with oHSV showed significant therapeutic improvement as the result of oHSV compared with wild-type mice. Combination of virotherapy with CD73 antibody blockade also resulted in enhanced antitumor efficacy. CONCLUSIONS: Here, we identify that immunosuppressive eADO signaling in the TME is a major barrier to oHSV therapy and CD73 blockade prevents tumor immune escape. The combination of oHSV with CD73 blockade supports the development of an antitumor immune memory response in solid tumors. This study supports clinical development of this combination strategy.

Author Info: (1) Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, Texas, USA. Pathology, Augusta University Medical College of Georgia, Augusta, G

Author Info: (1) Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, Texas, USA. Pathology, Augusta University Medical College of Georgia, Augusta, Georgia, USA. (2) Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina, USA. Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA. (3) Pathology, Augusta University Medical College of Georgia, Augusta, Georgia, USA. (4) Neurosurgery, The University of Texas Health Science Center, Houston, Texas, USA. (5) Neurosurgery, LSU Health New Orleans, New Orleans, Louisiana, USA. (6) Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina, USA. Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA. (7) Biochemistry & Molecular Biology, Augusta University Medical College of Georgia, Augusta, Georgia, USA. (8) Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA. (9) Pathology, Augusta University Medical College of Georgia, Augusta, Georgia, USA bkaur@augusta.edu.

Citation: J Immunother Cancer 2026 Jan 8 14: Epub01/08/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41506791

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Retargeted oncolytic viruses engineered to remodel the tumor microenvironment for glioblastoma immunotherapy Spotlight 

(1) Giovannoni F (2) Strathdee CA (3) Faust Akl C (4) Andersen BM (5) Li Z (6) Lee HG (7) Torti MF (8) Rone JM (9) Duart-Abadia P (10) Molgora M (11) Kong L (12) Floyd M (13) Teng J (14) Gyulakian Y (15) Grezsik P (16) Farkaly T (17) Denslow A (18) Feau S (19) Rodriguez-Sanchez I (20) Jacques J (21) Colonna M (22) Kennedy EM (23) Cheema T (24) Lerner L (25) QuŽva C (26) Quintana FJ

Nature cancer

Giovannoni, Strathdee, and Akl et al. engineered an HSV-1 platform for GBM viroimmunotherapy. Incorporation of EGFR- or integrin-binding gD variants expanded GBM tropism, fusogenic mutations enhanced intratumoral spread, and miRNA attenuation protected healthy CNS tissue. The replication-competent backbone enabled local delivery of IL-12, anti-PD-1, a bispecific T cell engager, HPGD to degrade PGE2, and anti-TREM2 to remodel lymphoid and myeloid compartments. Single intratumoral dosing elicited tumor-specific T cell, NK cell, and myeloid responses, and prolonged survival in aGL261-N GBM model.

Contributed by Shishir Pant

(1) Giovannoni F (2) Strathdee CA (3) Faust Akl C (4) Andersen BM (5) Li Z (6) Lee HG (7) Torti MF (8) Rone JM (9) Duart-Abadia P (10) Molgora M (11) Kong L (12) Floyd M (13) Teng J (14) Gyulakian Y (15) Grezsik P (16) Farkaly T (17) Denslow A (18) Feau S (19) Rodriguez-Sanchez I (20) Jacques J (21) Colonna M (22) Kennedy EM (23) Cheema T (24) Lerner L (25) QuŽva C (26) Quintana FJ

Nature cancer

Giovannoni, Strathdee, and Akl et al. engineered an HSV-1 platform for GBM viroimmunotherapy. Incorporation of EGFR- or integrin-binding gD variants expanded GBM tropism, fusogenic mutations enhanced intratumoral spread, and miRNA attenuation protected healthy CNS tissue. The replication-competent backbone enabled local delivery of IL-12, anti-PD-1, a bispecific T cell engager, HPGD to degrade PGE2, and anti-TREM2 to remodel lymphoid and myeloid compartments. Single intratumoral dosing elicited tumor-specific T cell, NK cell, and myeloid responses, and prolonged survival in aGL261-N GBM model.

Contributed by Shishir Pant

ABSTRACT: Glioblastoma (GBM) is an aggressive, immunotherapy-resistant brain tumor. Here, we engineered an oncolytic virus platform based on herpes simplex virus 1 for GBM viroimmunotherapy. We mutated the highly cytopathic MacIntyre strain to increase spread and oncolytic activity, limit genetic drift, prevent neuron infection and enable PET tracing. We incorporated microRNA target cassettes to attenuate replication in healthy brain cells. Moreover, we engineered the gD envelope protein to specifically target GBM using EGFR-specific or integrin-specific binders. Lastly, we incorporated five immunomodulators to remodel the tumor microenvironment (TME) by locally expressing IL-12, anti-PD1, a bispecific T cell engager, 15-hydroxyprostaglandin dehydrogenase and anti-TREM2 to target T cells and myeloid cells in the GBM TME. A single intratumoral injection increased survival in GBM preclinical models, while promoting tumor-specific T cell, natural killer cell and myeloid cell responses in the TME. In summary, we engineered a retargeted, safe and traceable oncolytic virus with strong cytotoxic and immunostimulatory activities for GBM immunotherapy.

Author Info: (1) Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (2) Oncorus, Inc., Andover, MA, USA. (3) Ann Romney Center for

Author Info: (1) Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (2) Oncorus, Inc., Andover, MA, USA. (3) Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Faculty of Biology, University of Freiburg, Freiburg, Germany. (4) Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Department of Neurology, Veterans Affairs Medical Center, Harvard Medical School, Boston, MA, USA. (5) Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (6) Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (7) Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (8) Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (9) Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. (10) Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA. (11) Oncorus, Inc., Andover, MA, USA. (12) Oncorus, Inc., Andover, MA, USA. (13) Oncorus, Inc., Andover, MA, USA. (14) Oncorus, Inc., Andover, MA, USA. (15) Oncorus, Inc., Andover, MA, USA. (16) Oncorus, Inc., Andover, MA, USA. (17) Oncorus, Inc., Andover, MA, USA. (18) Oncorus, Inc., Andover, MA, USA. (19) Oncorus, Inc., Andover, MA, USA. (20) Oncorus, Inc., Andover, MA, USA. (21) Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA. (22) Oncorus, Inc., Andover, MA, USA. (23) Oncorus, Inc., Andover, MA, USA. (24) Oncorus, Inc., Andover, MA, USA. (25) Oncorus, Inc., Andover, MA, USA. christophe@ovietx.com. (26) Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. fquintana@rics.bwh.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. fquintana@rics.bwh.harvard.edu. The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. fquintana@rics.bwh.harvard.edu.

Citation: Nat Cancer 2025 Dec 4 Epub12/04/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41345806

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Engineered bacteria launch and control an oncolytic virus Spotlight 

(1) Singer ZS (2) Pab—n J (3) Huang H (4) Sun W (5) Luo H (6) Grant KR (7) Obi I (8) Coker C (9) Rice CM (10) Danino T

Nature biomedical engineering

Singer and Pabón et al. developed a Salmonella typhimurium bacterial platform that delivered non-spreading, self-replicating viral RNA, even into cell types beyond the virus’s natural tropism. S. typhimurium “encapsidating” full-length oncolytic Senecavirus A delivered i.t. into s.c. engrafted tumors cleared treated and distal tumors in athymic mice, as did i.v. treatment of immunocompetent mice (even in the presence of pre-existing circulating viral-neutralizing antibodies), without adverse effects. Additional virus engineering aimed to control viral spread and persistence and to mitigate RNA mutational escape by requiring that virion maturation depend on bacterially delivered TEV protease.

Contributed by Paula Hochman

(1) Singer ZS (2) Pab—n J (3) Huang H (4) Sun W (5) Luo H (6) Grant KR (7) Obi I (8) Coker C (9) Rice CM (10) Danino T

Nature biomedical engineering

Singer and Pabón et al. developed a Salmonella typhimurium bacterial platform that delivered non-spreading, self-replicating viral RNA, even into cell types beyond the virus’s natural tropism. S. typhimurium “encapsidating” full-length oncolytic Senecavirus A delivered i.t. into s.c. engrafted tumors cleared treated and distal tumors in athymic mice, as did i.v. treatment of immunocompetent mice (even in the presence of pre-existing circulating viral-neutralizing antibodies), without adverse effects. Additional virus engineering aimed to control viral spread and persistence and to mitigate RNA mutational escape by requiring that virion maturation depend on bacterially delivered TEV protease.

Contributed by Paula Hochman

ABSTRACT: The ability of bacteria and viruses to selectively replicate in tumours has led to synthetic engineering of new microbial therapies. Here we design a cooperative strategy whereby Salmonella typhimurium bacteria transcribe and deliver the Senecavirus A RNA genome inside host cells, launching a potent oncolytic viral infection. 'Encapsidated' by bacteria, the viral genome can further bypass circulating antiviral antibodies to reach the tumour and initiate replication and spread within immune mice. Finally, we engineer the virus to require a bacterially delivered protease to achieve virion maturation, demonstrating bacterial control over the virus. Together, we refer to this platform as 'CAPPSID' for Coordinated Activity of Prokaryote and Picornavirus for Safe Intracellular Delivery. This work extends bacterially delivered therapeutics to viral genomes, and shows how a consortium of microbes can achieve a cooperative aim.

Author Info: (1) Department of Biomedical Engineering, Columbia University, New York, NY, USA. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA. (2)

Author Info: (1) Department of Biomedical Engineering, Columbia University, New York, NY, USA. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA. (2) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (3) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (4) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (5) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (6) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (7) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (8) Department of Biomedical Engineering, Columbia University, New York, NY, USA. (9) Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA. (10) Department of Biomedical Engineering, Columbia University, New York, NY, USA. tal.danino@columbia.edu. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. tal.danino@columbia.edu. Data Science Institute, Columbia University, New York, NY, USA. tal.danino@columbia.edu.

Citation: Nat Biomed Eng 2025 Aug 15 Epub08/15/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40817284

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Targeting the CD40 costimulatory receptor to improve virotherapy efficacy in diffuse midline gliomas Spotlight 

(1) Labiano S (2) Marco-Sanz J (3) Ausejo-Mauleon I (4) Laspidea V (5) Hernndez-Osuna R (6) Garcia-Moure M (7) Nava D (8) Nuin S (9) Gonzalez-Huarriz M (10) Phoenix TN (11) Tamayo I (12) Zalacain M (13) Lacalle A (14) Marrodan L (15) Puigdelloses M (16) Hervs-Corpin I (17) Ochoa MC (18) Casares N (19) Becher OJ (20) Gomez-Manzano C (21) Fueyo J (22) Perez-Larraya JG (23) Patiño-Garcia A (24) Alonso MM

Cell reports. Medicine

Labiano et al. showed that in mice with diffuse midline glioma (DMG), intratumoral co-administration of the Delta-24-RGD oncolytic virus and agonist CD40 antibodies extended survival and induced complete responses in 40% of mice, with protection from rechallenge that was dependent on local and resident immune memory. No signs of toxicity were observed. Mechanistically, treatment induced TME remodeling towards a pro-inflammatory landscape. Macrophage and microglia mediated recruitment of mature, cross-presenting cDC1s that supported the accumulation of activated and proliferating CD4+ and CD8+ TILs in tumors.

Contributed by Lauren Hitchings

(1) Labiano S (2) Marco-Sanz J (3) Ausejo-Mauleon I (4) Laspidea V (5) Hernndez-Osuna R (6) Garcia-Moure M (7) Nava D (8) Nuin S (9) Gonzalez-Huarriz M (10) Phoenix TN (11) Tamayo I (12) Zalacain M (13) Lacalle A (14) Marrodan L (15) Puigdelloses M (16) Hervs-Corpin I (17) Ochoa MC (18) Casares N (19) Becher OJ (20) Gomez-Manzano C (21) Fueyo J (22) Perez-Larraya JG (23) Patiño-Garcia A (24) Alonso MM

Cell reports. Medicine

Labiano et al. showed that in mice with diffuse midline glioma (DMG), intratumoral co-administration of the Delta-24-RGD oncolytic virus and agonist CD40 antibodies extended survival and induced complete responses in 40% of mice, with protection from rechallenge that was dependent on local and resident immune memory. No signs of toxicity were observed. Mechanistically, treatment induced TME remodeling towards a pro-inflammatory landscape. Macrophage and microglia mediated recruitment of mature, cross-presenting cDC1s that supported the accumulation of activated and proliferating CD4+ and CD8+ TILs in tumors.

Contributed by Lauren Hitchings

ABSTRACT: Diffuse midline glioma (DMG) is a devastating pediatric brain tumor. The oncolytic adenovirus Delta-24-RGD has shown promising efficacy and safety in DMG patients but is not yet curative. Thus, we hypothesized that activating dendritic cells (DCs) through the CD40 costimulatory receptor could increase antigen presentation and enhance the anti-tumor effect of the virus, resulting in long-term responses. This study shows that the intratumoral co-administration of Delta-24-RGD and a CD40 agonistic antibody is well tolerated and induces long-term anti-tumor immunity, including complete responses (up to 40%) in DMG preclinical models. Mechanistic studies revealed that this therapy increased tumor-proliferating T lymphocytes and proinflammatory myeloid cells, including mature DCs with superior tumor antigen uptake capacity. Moreover, the lack of cross-presenting DCs and the prevention of DC recruitment into the tumor abolish the Delta-24-RGD+anti-CD40 anti-DMG effect. This approach shows potential for combining virotherapy with activating antigen-presenting cells in these challenging tumors.

Author Info: (1) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pampl

Author Info: (1) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. Electronic address: slalminana@unav.es. (2) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (3) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (4) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (5) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (6) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (7) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (8) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (9) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (10) Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA. (11) Bioinformatics Platform, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain. (12) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (13) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (14) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (15) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (16) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (17) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (18) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (19) Jack Martin Fund Division of Pediatric Hematology-oncology, Mount Sinai, New York, NY, USA. (20) Dpt. Of NeuroOncology, UT MD Anderson Cancer Center, Houston, TX, USA. (21) Dpt. Of NeuroOncology, UT MD Anderson Cancer Center, Houston, TX, USA. (22) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (23) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. (24) Department of Pediatrics, Clinica Universidad de Navarra, Pamplona, Spain; Program in Solid Tumors, Center for the Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Health Research Institute of Navarra (IdiSNA), Pamplona, Navarra, Spain. Electronic address: mmalonso@unav.es.

Citation: Cell Rep Med 2025 Jun 23 102204 Epub06/23/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40578365

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Oncolytic virus OH2 extends survival in patients with PD-1 pretreated melanoma: phase Ia/Ib trial results and biomarker insights

(1) Wang X (2) Tian H (3) Chi Z (4) Si L (5) Sheng X (6) Hu H (7) Gu X (8) Li S (9) Li C (10) Lian B (11) Zhou L (12) Mao L (13) Tang B (14) Yan X (15) Wei X (16) Li J (17) Liu B (18) Guo J (19) Kong Y (20) Cui C

Journal for immunotherapy of cancer

(1) Wang X (2) Tian H (3) Chi Z (4) Si L (5) Sheng X (6) Hu H (7) Gu X (8) Li S (9) Li C (10) Lian B (11) Zhou L (12) Mao L (13) Tang B (14) Yan X (15) Wei X (16) Li J (17) Liu B (18) Guo J (19) Kong Y (20) Cui C

Journal for immunotherapy of cancer

BACKGROUND: OH2 is an oncolytic virus derived from herpes simplex virus type 2. A phase Ia/Ib clinical trial in China was conducted in patients with unresected stage III-IV melanoma, the majority of whom had the acral type, to assess the safety and preliminary efficacy of OH2. METHODS: The trial enrolled patients with histologically confirmed unresectable stage III or advanced stage IV melanoma. In phase Ia, nine patients received OH2 single-dose treatment across three dose levels (10(6), 10(7), and 10(8) CCID(50)/mL, where CCID(50) represents cell culture infectious dose 50%) while six patients underwent multidose therapy. Phase Ib expanded the proposed dose. Antitumor efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors and immune-RECIST guidelines. NCT04386967 is the clinical trial identifier. RESULTS: All 44 patients were enrolled. OH2 was well tolerated without serious adverse events (AEs) or deaths reported. No Grade 3 or higher treatment-related AEs occurred. In phase Ia, the 1-year survival rate was 92.9% (95% CI, 59.1% to 99.0%), with a median overall survival of 28.9 months (95%_CI, 12.7 to not reached). In phase Ib, 10 patients achieved immune-partial response (iPR)/partial response (PR), yielding an objective response rate (ORR) of 37.0% (95% CI, 19.4% to 57.6%), with 6 patients still responding. The rate of the durable response (PR or complete response lasting at least 6 months) was at least 29.6% (8/27). Notably, 7 of 12 III-IVM1a patients who previously received programmed cell death protein-1 (PD-1) therapy achieved iPR/PR, with an ORR of 58.3% (95% CI, 27.7% to 84.8%) and a disease control rate of 75.0% (95% CI, 42.8% to 94.5%). Biomarker analysis indicated that elevated baseline neutrophil activation state correlated with poorer clinical outcomes. A phase III clinical trial is ongoing in China (NCT05868707). CONCLUSIONS: OH2 oncolytic virotherapy exhibited a favorable safety profile without dose-limiting toxicities (DLTs) and demonstrated durable antitumor efficacy in patients with melanoma, especially in those who had progressed on anti-PD-1 treatment. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT04386967.

Author Info: (1) Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing)_Peking University Cancer Hospital, Beijing, Chi

Author Info: (1) Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing)_Peking University Cancer Hospital, Beijing, China. (2) Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing)_Peking University Cancer Hospital, Beijing, China. (3) Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing)_Peking University Cancer Hospital, Beijing, China. (4) Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing)_Peking University Cancer Hospital, Beijing, China. (5) Department of Genitourinary Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University CancerHospital, Beijing, China. (6) National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Hubei University of Technology, Wuhan, Hubei, China. (7) Wuhan Binhui Biopharmaceutical Co., Ltd, Wuhan, Hubei, China. (8) Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing)_Peking University Cancer Hospital, Beijing, China. (9) Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing)_Peking University Cancer Hospital, Beijing, China. (10) Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing)_Peking University Cancer Hospital, Beijing, China. (11) Department of Genitourinary Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University CancerHospital, Beijing, China. (12) Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing)_Peking University Cancer Hospital, Beijing, China. (13) Department of Genitourinary Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University CancerHospital, Beijing, China. (14) Department of Genitourinary Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University CancerHospital, Beijing, China. (15) Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing)_Peking University Cancer Hospital, Beijing, China. (16) Department of Genitourinary Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University CancerHospital, Beijing, China. (17) Wuhan Binhui Biopharmaceutical Co., Ltd, Wuhan, Hubei, China. (18) Department of Genitourinary Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University CancerHospital, Beijing, China. (19) Department of Melanoma and Sarcoma, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing)_Peking University Cancer Hospital, Beijing, China 1008ccl@163.com k-yan08@163.com. (20) Department of Genitourinary Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University CancerHospital, Beijing, China 1008ccl@163.com k-yan08@163.com.

Citation: J Immunother Cancer 2025 Feb 6 13: Epub02/06/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39915002

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GM-CSF and IL-21-armed oncolytic vaccinia virus significantly enhances anti-tumor activity and synergizes with anti-PD1 immunotherapy in pancreatic cancer

(1) Xuan Y (2) Yan W (3) Wang R (4) Wang X (5) Guo Y (6) Dun H (7) Huan Z (8) Xu L (9) Han R (10) Sun X (11) Si L (12) Lemoine NR (13) Wang Y (14) Wang P

Frontiers in immunology | Free PMC Article

(1) Xuan Y (2) Yan W (3) Wang R (4) Wang X (5) Guo Y (6) Dun H (7) Huan Z (8) Xu L (9) Han R (10) Sun X (11) Si L (12) Lemoine NR (13) Wang Y (14) Wang P

Frontiers in immunology | Free PMC Article

Pancreatic cancer is one of the most aggressive cancers and poses significant challenges to current therapies because of its complex immunosuppressive tumor microenvironment (TME). Oncolytic viruses armed with immunoregulatory molecules are promising strategies to overcome limited efficacy and target inaccessible and metastatic tumors. In this study, we constructed a tumor-selective vaccinia virus (VV) with deletions of the TK and A49 genes (VVL_TK_A49, VVL-DD) using CRISPR-Cas9-based homologous recombination. VVL-DD exhibited significant tumor selectivity in vitro and anti-tumor potency in vivo in a murine pancreatic cancer model. Then, VVL-DD was armed with an optimal combination of immunomodulatory molecules, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-21 (IL-21), to produce VVL-GL21. VVL-GL21 induced significant tumor regression after intratumoral and systemic administration. Moreover, VVL-GL21 increased the infiltration of dendritic cells (DCs), macrophages, and T cells; induced DC maturation; increased the transition from M2 to M1 macrophages; improved the formation of immune memory; prevented tumor recurrence; and effectively bolstered the immune response against tumors in multiple key immune compartments. Interestingly, mice bearing-pancreatic cancer tumors treated with VVL-GL21 showed anti-tumor immunity against lung and colon cancer tumors. Importantly, treatment with VVL-GL21 enhanced the responsiveness of tumors to the immune checkpoint inhibitor anti-PD1. Taken together, VVL-GL21 remodels the suppressive TME and has powerful anti-tumor activities as monotherapy or in combination with anti-PD1 by intratumoral or systemic delivery for the treatment of pancreatic cancer. VVL-GL21 could be used as a therapeutic cancer vaccine.

Author Info: (1) Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention &

Author Info: (1) Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. (2) Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. (3) Department of Pathology, Zhengzhou People's Hospital, Fifth Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou, China. (4) Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. (5) Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. (6) Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. (7) Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. (8) Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. (9) Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. (10) Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. (11) Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. (12) Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. Centre for Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. (13) Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. Centre for Biomarkers & Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. (14) Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.

Citation: Front Immunol 2024 15:1506632 Epub01/03/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39830516

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Hyperacute rejection-engineered oncolytic virus for interventional clinical trial in refractory cancer patients Spotlight 

(1) Zhong L (2) Gan L (3) Wang B (4) Wu T (5) Yao F (6) Gong W (7) Peng H (8) Deng Z (9) Xiao G (10) Liu X (11) Na J (12) Xia D (13) Yu X (14) Zhang Z (15) Xiang B (16) Huo Y (17) Yan D (18) Dong Z (19) Fang F (20) Ma Y (21) Jin G (22) Su D (23) Liu X (24) Li Q (25) Liao H (26) Tang C (27) He J (28) Tang Z (29) Zhang S (30) Qiu B (31) Yang Z (32) Yang L (33) Chen Z (34) Zeng M (35) Feng R (36) Jiao J (37) Liao Y (38) Wang T (39) Wu L (40) Mi Z (41) Liu Z (42) Shi S (43) Zhang K (44) Shi W (45) Zhao Y

Cell

Zhong, Gan, Wang, and Wu et al. developed a recombinant Newcastle disease virus with a 1,3GT gene (NDV-GT) encoding porcine alpha-galactosidase (α-Gal) – an antigen that triggers the rejection of xenografts in primates. In cynomolgus monkeys with primary HCC induced by CRISPR, i.v. delivery of NDV-GT induced hyperacute rejection, altered tumor vasculature, triggered humoral and cellular immune responses, and reduced suppressive features in the TME, leading to regression of primary tumors and prolonged survival. In a clinical trial of 20 patients with diverse refractory cancer types, NDV-GT provided a 90% disease control rate without serious AEs.

Contributed by Lauren Hitchings

(1) Zhong L (2) Gan L (3) Wang B (4) Wu T (5) Yao F (6) Gong W (7) Peng H (8) Deng Z (9) Xiao G (10) Liu X (11) Na J (12) Xia D (13) Yu X (14) Zhang Z (15) Xiang B (16) Huo Y (17) Yan D (18) Dong Z (19) Fang F (20) Ma Y (21) Jin G (22) Su D (23) Liu X (24) Li Q (25) Liao H (26) Tang C (27) He J (28) Tang Z (29) Zhang S (30) Qiu B (31) Yang Z (32) Yang L (33) Chen Z (34) Zeng M (35) Feng R (36) Jiao J (37) Liao Y (38) Wang T (39) Wu L (40) Mi Z (41) Liu Z (42) Shi S (43) Zhang K (44) Shi W (45) Zhao Y

Cell

Zhong, Gan, Wang, and Wu et al. developed a recombinant Newcastle disease virus with a 1,3GT gene (NDV-GT) encoding porcine alpha-galactosidase (α-Gal) – an antigen that triggers the rejection of xenografts in primates. In cynomolgus monkeys with primary HCC induced by CRISPR, i.v. delivery of NDV-GT induced hyperacute rejection, altered tumor vasculature, triggered humoral and cellular immune responses, and reduced suppressive features in the TME, leading to regression of primary tumors and prolonged survival. In a clinical trial of 20 patients with diverse refractory cancer types, NDV-GT provided a 90% disease control rate without serious AEs.

Contributed by Lauren Hitchings

ABSTRACT: Recently, oncolytic virus (OV) therapy has shown great promise in treating malignancies. However, intravenous safety and inherent lack of immunity are two significant limitations in clinical practice. Herein, we successfully developed a recombinant Newcastle disease virus with porcine _1,3GT gene (NDV-GT) triggering hyperacute rejection. We demonstrated its feasibility in preclinical studies. The intravenous NDV-GT showed superior ability to eradicate tumor cells in our innovative CRISPR-mediated primary hepatocellular carcinoma monkeys. Importantly, the interventional clinical trial treating 20 patients with relapsed/refractory metastatic cancer (Chinese Clinical Trial Registry of WHO, ChiCTR2000031980) showed a high rate (90.00%) of disease control and durable responses, without serious adverse events and clinically functional neutralizing antibodies, further suggesting that immunogenicity is minimal under these conditions and demonstrating the feasibility of NDV-GT for immunovirotherapy. Collectively, our results demonstrate the high safety and efficacy of intravenous NDV-GT, thus providing an innovative technology for OV therapy in oncological therapeutics and beyond.

Author Info: (1) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China.

Author Info: (1) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. Electronic address: zhongliping@gxmu.edu.cn. (2) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (3) Department of Spine Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China. (4) The First People's Hospital of Changde City, Changde, Hunan 415000, China. (5) Department of Oncology, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, China. (6) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (7) The First People's Hospital of Changde City, Changde, Hunan 415000, China. (8) The First People's Hospital of Changde City, Changde, Hunan 415000, China. (9) Department of Nuclear Medicine, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (10) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (11) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (12) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (13) Department of Pancreatic Surgery, The Affiliated Tumor Hospital, Fudan University, Shanghai 200032, China. (14) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (15) Department of Hepatobiliary Surgery, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (16) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (17) Department of Oncology, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, China. (18) Department of Oncology, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, China. (19) Department of Oncology, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, China. (20) Department of Pathology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (21) Department of Radiology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (22) Department of Radiology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (23) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (24) Department of Radiology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (25) Department of Radiology, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (26) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (27) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (28) Department of Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China. (29) Department of Nuclear Medicine, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (30) Department of Nuclear Medicine, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (31) Department of Nuclear Medicine, The Affiliated Tumor Hospital, Guangxi Medical University, Nanning, Guangxi 530021, China. (32) Fundamental Nursing Teaching and Research Office, Nursing College of Guangxi Medical University, Nanning, Guangxi 530021, China. (33) The First People's Hospital of Changde City, Changde, Hunan 415000, China. (34) The First People's Hospital of Changde City, Changde, Hunan 415000, China. (35) The First People's Hospital of Changde City, Changde, Hunan 415000, China. (36) Yuandan Biotechnology (Hainan) Co., Ltd., Haikou, Hainan 570100, China. (37) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (38) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (39) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (40) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. (41) Department of Spine Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China. (42) Department of Pancreatic Surgery, The Affiliated Tumor Hospital, Fudan University, Shanghai 200032, China. (43) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. Electronic address: zhang1986kun@tongji.edu.cn. (44) Department of Oncology, The First Affiliated Hospital, Guangxi University of Chinese Medicine, Nanning, Guangxi 530023, China. Electronic address: shiwei1001@csco.org.cn. (45) State Key Laboratory of Targeting Oncology, National Center for International Research of Biotargeting Theranostics, Guangxi Medical University, Nanning, Guangxi 530021, China. Electronic address: zhaoyongxiang@gxmu.edu.cn.

Citation: Cell 2025 Jan 15 Epub01/15/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39826543

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A Novel Oncolytic Virus Formulation Based on Mesenchymal Stem Cell-Derived Vesicles for Tumor Therapy

(1) Zeng F (2) Huang Y (3) Xu B (4) Yao L (5) Zhang Y (6) Gao Z (7) Luo Y

Journal of Cancer | Free PMC Article

(1) Zeng F (2) Huang Y (3) Xu B (4) Yao L (5) Zhang Y (6) Gao Z (7) Luo Y

Journal of Cancer | Free PMC Article

Developing new drug delivery systems is crucial for enhancing the efficacy of oncolytic virus (OV) therapies in cancer treatment. In this study, mesenchymal stem cell (MSC)-derived vesicles and oncolytic viruses are exploited to construct a novel formulation. It has been hypothesized that vesicle-coated OVs could amplify cytotoxic effects through superior internalization by tumor cells. MSC vesicles possess natural tumor homing ability and biocompatibility, which can enhance the targeting, uptake, and therapeutic effects of OVs on tumor cells. Experimental results indicated that this treatment system has increased the apoptosis of tumor cells. Furthermore, flow cytometry analysis demonstrated that the uptake of tumor cells by OVs coated with MSC vesicles soared away compared to uncoated OVs, being 1.5 times than that of the uncoated group. Additionally, the confocal laser scanning microscopy also showed that the fluorescence intensity within tumor cells pretreated with MSC-coated OVs was greater. Meanwhile, propidium iodide (PI) staining revealed that MSC-coated Ovs exposed to tumor cells accelerating the apoptosis of the latter. According to the statistics, the number of dead cells was increased, and the flow cytometry testified that the apoptosis in the MSC-coated OV group was as high as 23.78%. These findings highlight the potential of MSC vesicle-coated OVs in enhancing the delivery and efficacy of oncolytic virus therapy, providing a promising strategy for cancer treatment.

Author Info: (1) Department of General Practice, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical Univ

Author Info: (1) Department of General Practice, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China. (2) School of Medicine, South China University of Technology, Department of Thoracic Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510006, China. (3) School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 510006, China. (4) Department of Thoracic Surgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China. (5) Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China. (6) Department of General Practice, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China. (7) Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu 214122, China.

Citation: J Cancer 2025 16:700-707 Epub01/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39781350

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