Journal Articles

Lung Cancer-Intrinsic SOX2 Expression Mediates Resistance to Checkpoint Blockade Therapy by Inducing Treg-Dependent CD8+ T-cell Exclusion

Torres-Mejia et al. showed that tumor cell-intrinsic SOX2 expression correlated with low T cell infiltration in NSCLC. Overexpression of SOX2 in tumor cells induced CD8+ T cell exclusion from the tumor core, and promoted tumor growth and resistance to anti-PD-1 and anti-CTLA-4 in the KP lung tumor model. SOX2 signaling upregulated CCL2 in tumor cells, resulting in increased recruitment of Tregs, which suppressed tumor vasculature, leading to CD8+ T cell exclusion from the tumor core. Anti-GITR treatment reduced Treg density within the TME, improved CD8+ T cell infiltration, and suppressed tumor growth when combined with checkpoint blockade.

Contributed by Shishir Pant

Torres-Mejia et al. showed that tumor cell-intrinsic SOX2 expression correlated with low T cell infiltration in NSCLC. Overexpression of SOX2 in tumor cells induced CD8+ T cell exclusion from the tumor core, and promoted tumor growth and resistance to anti-PD-1 and anti-CTLA-4 in the KP lung tumor model. SOX2 signaling upregulated CCL2 in tumor cells, resulting in increased recruitment of Tregs, which suppressed tumor vasculature, leading to CD8+ T cell exclusion from the tumor core. Anti-GITR treatment reduced Treg density within the TME, improved CD8+ T cell infiltration, and suppressed tumor growth when combined with checkpoint blockade.

Contributed by Shishir Pant

ABSTRACT: Tumor cell-intrinsic signaling pathways can drastically affect the tumor immune microenvironment, promoting tumor progression and resistance to immunotherapy by excluding immune cell populations from the tumor. Several tumor cell-intrinsic pathways have been reported to modulate myeloid-cell and T-cell infiltration, creating "cold" tumors. However, clinical evidence suggests that excluding cytotoxic T cells from the tumor core also mediates immune evasion. In this study, we find that tumor cell-intrinsic SOX2 signaling in non-small cell lung cancer induces the exclusion of cytotoxic T cells from the tumor core and promotes resistance to checkpoint blockade therapy. Mechanistically, tumor cell-intrinsic SOX2 expression upregulates CCL2 in tumor cells, resulting in increased recruitment of regulatory T cells (Treg). CD8+ T-cell exclusion depended on Treg-mediated suppression of tumor vasculature. Depleting tumor-infiltrating Tregs via glucocorticoid-induced TNF receptor-related protein restored CD8+ T-cell infiltration and, when combined with checkpoint blockade therapy, reduced tumor growth. These results show that tumor cell-intrinsic SOX2 expression in lung cancer serves as a mechanism of immunotherapy resistance and provide evidence to support future studies investigating whether patients with non-small cell lung cancer with SOX2-dependent CD8+ T-cell exclusion would benefit from the depletion of glucocorticoid-induced TNFR-related protein-positive Tregs.

Author Info: (1) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. (2) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. Wellesley Coll

Author Info: (1) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. (2) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. Wellesley College, Wellesley, Massachusetts. (3) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. (4) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. Department of Biology, MIT, Cambridge, Massachusetts. (5) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. Department of Biology, MIT, Cambridge, Massachusetts. (6) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. (7) Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. Department of Biology, MIT, Cambridge, Massachusetts. Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts.

Antitumor CD4+ T Helper 1 Cells Target and Control the Outgrowth of Disseminated Cancer Cells

Ramamoorthi et al. demonstrated that disseminated cancer cells (DCCs) in bone marrow exhibited a different gene expression profile (stemness and EMT) than primary and metastatic tumor cells in breast cancer. Intratumorally delivered cDC1s primed tumor antigen-specific CD4+ Th1 cells, which modestly controlled primary tumor growth, but were able to migrate into distant organs to eradicate DCC-driven metastases. The CD4+ Th1 cytokine IFNγ regulated cancer stemness, EMT, cell cycle, and cholesterol biosynthesis signatures to restrain the tumorigenic potential of DCCs, but failed to eradicate DCC-driven metastases in IFNγ KO mice.

Contributed by Shishir Pant

Ramamoorthi et al. demonstrated that disseminated cancer cells (DCCs) in bone marrow exhibited a different gene expression profile (stemness and EMT) than primary and metastatic tumor cells in breast cancer. Intratumorally delivered cDC1s primed tumor antigen-specific CD4+ Th1 cells, which modestly controlled primary tumor growth, but were able to migrate into distant organs to eradicate DCC-driven metastases. The CD4+ Th1 cytokine IFNγ regulated cancer stemness, EMT, cell cycle, and cholesterol biosynthesis signatures to restrain the tumorigenic potential of DCCs, but failed to eradicate DCC-driven metastases in IFNγ KO mice.

Contributed by Shishir Pant

ABSTRACT: Detection of disseminated cancer cells (DCC) in the bone marrow (BM) of patients with breast cancer is a critical predictor of late recurrence and distant metastasis. Conventional therapies often fail to completely eradicate DCCs in patients. In this study, we demonstrate that intratumoral priming of antitumor CD4+ T helper 1 (Th1) cells was able to eliminate the DCC burden in distant organs and prevent overt metastasis, independent of CD8+ T cells. Intratumoral priming of tumor antigen-specific CD4+ Th1 cells enhanced their migration to the BM and distant metastatic site to selectively target DCC burden. The majority of these intratumorally activated CD4+ T cells were CD4+PD1- T cells, supporting their nonexhaustion stage. Phenotypic characterization revealed enhanced infiltration of memory CD4+ T cells and effector CD4+ T cells in the primary tumor, tumor-draining lymph node, and DCC-driven metastasis site. A robust migration of CD4+CCR7+CXCR3+ Th1 cells and CD4+CCR7-CXCR3+ Th1 cells into distant organs further revealed their potential role in eradicating DCC-driven metastasis. The intratumoral priming of antitumor CD4+ Th1 cells failed to eradicate DCC-driven metastasis in CD4- or IFN-_ knockout mice. Moreover, antitumor CD4+ Th1 cells, by increasing IFN-_ production, inhibited various molecular aspects and increased classical and nonclassical MHC molecule expression in DCCs. This reduced stemness and self-renewal while increasing immune recognition in DCCs of patients with breast cancer. These results unveil an immune basis for antitumor CD4+ Th1 cells that modulate DCC tumorigenesis to prevent recurrence and metastasis in patients.

Author Info: (1) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (2) Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida. (3) Department of Breast

Author Info: (1) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (2) Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida. (3) Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida. (4) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (5) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (6) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (7) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (8) Small Animal Imaging Laboratory Core, Moffitt Cancer Center, Tampa, Florida. (9) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (10) Department of Pathology, Moffitt Cancer Center, Tampa, Florida. (11) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (12) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (13) Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida. (14) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (15) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. (16) Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida. (17) Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida. (18) Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, Florida. (19) Clinical Science & Immunology Program, Moffitt Cancer Center, Tampa, Florida. Department of Breast Oncology, Moffitt Cancer Center, Tampa, Florida.

Targeting cancer-associated glycosylation for adoptive T cell therapy of solid tumors

Based on the highly specific 2G12-2B2 antibody, Zingg et al. generated a fully human CAR targeting sialyl-Thomsen-Nouveau antigen (STn), which was expressed at high levels in colon, pancreatic, and gynecological cancers compared to healthy tissues. In vitro, CAR T cells with CD28 and 4-1BB costimulatory domains, but not TRuC constructs, were cytotoxic over longer periods of time, even at low effector:target cell ratios or at native antigen expression levels. In mice, CAR T cells with CD28 showed increased tumor infiltration and induced long-term tumor control and some cures, without considerable toxicity, despite some luminal expression of STn in healthy gastrointestinal tissues.

Contributed by Lauren Hitchings

Based on the highly specific 2G12-2B2 antibody, Zingg et al. generated a fully human CAR targeting sialyl-Thomsen-Nouveau antigen (STn), which was expressed at high levels in colon, pancreatic, and gynecological cancers compared to healthy tissues. In vitro, CAR T cells with CD28 and 4-1BB costimulatory domains, but not TRuC constructs, were cytotoxic over longer periods of time, even at low effector:target cell ratios or at native antigen expression levels. In mice, CAR T cells with CD28 showed increased tumor infiltration and induced long-term tumor control and some cures, without considerable toxicity, despite some luminal expression of STn in healthy gastrointestinal tissues.

Contributed by Lauren Hitchings

ABSTRACT: CAR T-cell therapy has improved outcomes for patients with chemotherapy-resistant B-cell malignancies. However, CAR T-cell treatment of patients with solid cancers has been more difficult, in part because of the heterogeneous expression of tumor-specific cell surface antigens. Here, we describe the generation of a fully human CAR targeting altered glycosylation in secretory epithelial cancers. The expression of the target antigen - the truncated, sialylated O-glycan sialyl-Thomsen-Nouveau antigen (STn) - was studied with a highly STn-specific antibody across various different tumor tissues. Strong expression was found in a high proportion of gastro-intestinal cancers including pancreatic cancers and in gynecological cancers, in particular ovarian and endometrial tumors. T cells expressing anti-STn CAR were tested in vitro and in vivo. Anti-STn CAR T cells showed activity in mouse models as well as in assays with primary ovarian cancer samples. No considerable toxicity was observed in mouse models, although some intraluminal expression of STn was found in gastro-intestinal mouse tissue. Taken together, this fully human anti-STn CAR construct shows promising activity in preclinical tumor models supporting its further evaluation in early clinical trials.

Author Info: (1) University of Basel, Basel, Switzerland. (2) University of Basel, Basel, Switzerland. (3) University of Basel, Basel, Switzerland. (4) Cancer Immunology, Department of Biomedic

Author Info: (1) University of Basel, Basel, Switzerland. (2) University of Basel, Basel, Switzerland. (3) University of Basel, Basel, Switzerland. (4) Cancer Immunology, Department of Biomedicine, University of Basel, Switzerland. (5) University of Basel, Basel, Switzerland. (6) University of Basel, Basel, Switzerland. (7) University Hospital of Basel, Basel, Switzerland. (8) University of Basel, Basel, Switzerland. (9) Division of Medical Oncology, University Hospital Basel, Basel, Switzerland. (10) University Hospital of Basel, Basel, Switzerland. (11) University of Basel, Basel, Switzerland. (12) University Hospital of Basel, Switzerland. (13) University of Basel, Basel, Switzerland.

Safety and feasibility of 4-1BB co-stimulated CD19-specific CAR-NK cell therapy in refractory/relapsed large B cell lymphoma: a phase 1 trial

In a phase 1 trial, Lei et al. investigated CD19-BBz CAR NK cells, derived from cord blood and engineered to express IL-15, in 8 patients with relapsed/refractory large B cell lymphoma. Three weekly infusions of CAR-NK did not lead to cytokine release syndrome, GvHD, or neurotoxicity. The 30-day ORR was 62.5%, and 50% of patients achieved a CR. The median PFS was 9.5 months, and two patients continued to show durable responses at 25 months. CAR copies were detectable in the peripheral blood of one patient with CR for 15 months. Transcriptome analysis indicated that inhibiting CBLB-mediated ubiquitination may enhance CAR-NK cell efficacy.

Contributed by Ute Burkhardt

In a phase 1 trial, Lei et al. investigated CD19-BBz CAR NK cells, derived from cord blood and engineered to express IL-15, in 8 patients with relapsed/refractory large B cell lymphoma. Three weekly infusions of CAR-NK did not lead to cytokine release syndrome, GvHD, or neurotoxicity. The 30-day ORR was 62.5%, and 50% of patients achieved a CR. The median PFS was 9.5 months, and two patients continued to show durable responses at 25 months. CAR copies were detectable in the peripheral blood of one patient with CR for 15 months. Transcriptome analysis indicated that inhibiting CBLB-mediated ubiquitination may enhance CAR-NK cell efficacy.

Contributed by Ute Burkhardt

ABSTRACT: Chimeric antigen receptor (CAR)-modified NK (CAR-NK) cells are candidates for next-generation cancer immunotherapies. Here we generated CD19-specific CAR-NK cells with 4-1BB and CD3_ signaling endo-domains (CD19-BBz CAR-NK) by transduction of cord blood-derived NK cells using baboon envelope pseudotyped lentiviral vectors and demonstrated their antitumor activity in preclinical B cell lymphoma models in female mice. We next conducted a phase 1 dose-escalation trial involving repetitive administration of CAR-NK cells in 8 patients with relapsed/refractory large B cell lymphoma (NCT05472558). Primary end points were safety, maximum tolerated dose, and overall response rate. Secondary end points included duration of response, overall survival, and progression-free survival. No dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. No cases of cytokine release syndrome, neurotoxicity, or graft-versus-host disease were observed. Results showed an overall response rate of 62.5% at day 30, with 4 patients (50%) achieving complete response. The median progression-free survival was 9.5_months, and the median overall survival was not reached. A post hoc exploratory single-cell RNA sequencing analysis revealed molecular features of CAR-NK cells associated with therapeutic efficacy and efficacy-related immune cell interaction networks. This study met the pre-specified end points. In conclusion, CD19-BBz CAR-NK cells were feasible and therapeutically safe, capable of inducing durable response in patients with B cell lymphoma.

Author Info: (1) Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Key Laboratory of Cancer Prevention and Intervention, China

Author Info: (1) Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education; Biotherapy Research Center, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. (2) Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. (3) Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, China. (4) Stem Cell Translational Research Center, Tongji Hospital, Tongji University, School of Medicine, Shanghai, China. (5) Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. (6) Stem Cell Translational Research Center, Tongji Hospital, Tongji University, School of Medicine, Shanghai, China. (7) Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. (8) Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. (9) Department of Hematology, Tongji Hospital of Tongji University, Shanghai, China. (10) State Key Laboratory of Stem Cell and Reproductive Biology, Institute for Stem Cell and Regeneration, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. (11) Department of Hematology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China. tongxiangmin@163.com. (12) Stem Cell Translational Research Center, Tongji Hospital, Tongji University, School of Medicine, Shanghai, China. yi.eve.sun@gmail.com. (13) Department of Hematology, Tongji Hospital of Tongji University, Shanghai, China. lab7182@tongji.edu.cn. (14) Department of Hematology, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. qianwb@zju.edu.cn. Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education; Biotherapy Research Center, the Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. qianwb@zju.edu.cn.

Cancer vaccine momentum builds, but US funding cuts raise concerns

NO ABSTRACT

Author Info: -1

Author Info: -1

CD28-costimulated CD19 CAR-T cells for pediatric mature non-Hodgkin B-cell lymphoma

Children with relapsed or refractory (R/R) mature B-cell non-Hodgkin lymphoma (B-NHL) have a poor prognosis with approved therapies. Chimeric antigen receptor (CAR)-T cells are approved for adults with R/R B-NHL, but pediatric data is lacking. We report on 13 children with R/R mature B-NHL enrolled on a clinical trial for CD19 CAR-T cells harboring CD28 costimulation. Twelve patients were infused with CAR-T cells, and one had progressed and died prior to infusion. Toxicities included cytokine release syndrome in 8 patients and neurotoxicity in 6, including two patients with grade 4 neurotoxicity. All patients responded to CAR-T cells, including a complete response in 6, complete metabolic response in 2 and partial response in four. The median event-free survival was 15.2 months and median overall survival was not reached. Outcome differed by disease type, as most patients with primary mediastinal B-cell lymphoma had long term remissions, while only two of seven patients with Burkitt lymphoma were long term survivors. Thus, initial response may suffice for certain patients, but further consolidative strategies should be studied in patients with R/R Burkitt lymphoma.

Author Info: (1) Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel. Faculty of Medical & Health Sciences,

Author Info: (1) Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel. Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel. (2) Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel. Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel. (3) Department of Pediatric Hematology-Oncology, Rambam Medical Center, and The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. (4) Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel. (5) Ella Institute of Immuno-Oncology, Sheba Medical Center, Tel Hashomer, Israel. (6) Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel. Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel. (7) Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel. Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel. (8) Division of Pediatric Hematology and Oncology, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel. elad.jacoby@sheba.health.gov.il. Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel. elad.jacoby@sheba.health.gov.il.

Exosome-based cancer vaccine: a cell-free approach

Despite advancements in medical research, cancer remains a significant and persistent cause of death globally. Cancer vaccine, a novel approach, holds immense promise in development of potentially effective cancer treatment. While the concept of developing cancer vaccines has been explored for decades, significant challenges have hindered their clinical translation. Recent researchers have introduced exosomes as the key element for novel cell-free approach of cancer vaccines. Exosomes are a type of extracellular vesicle (EVs) secreted by various cells. These tiny structures can transport and deliver important biomolecules, such as DNA, RNA, proteins, lipids, and immune-stimulatory molecules, to stimulate the body's anti-tumor immune response. Their biocompatibility, targeting ability, immunogenicity, and a notable capacity to cross biological barriers nominate them as promising candidates for cancer vaccine development by addressing current challenges in cancer therapy. This review explores the current state of knowledge on the efficacy of exosomes from various sources for personalized cancer vaccine development, preclinical and clinical evaluations, along with the strategies to optimize immunogenicity and antigen presentation. We also discuss the challenges and potential solutions for overcoming tumor microenvironment-related hurdles, highlighting the promise of exosome-based approaches for cancer immunotherapy by developing a novel cell-free cancer vaccine in future.

Author Info: (1) Department of Oncology, Neuron Institute of Applied Research, Amravati, Maharashtra, India. (2) Department of Oncology, Neuron Institute of Applied Research, Amravati, Maharash

Author Info: (1) Department of Oncology, Neuron Institute of Applied Research, Amravati, Maharashtra, India. (2) Department of Oncology, Neuron Institute of Applied Research, Amravati, Maharashtra, India. (3) Department of Oncology, Neuron Institute of Applied Research, Amravati, Maharashtra, India. (4) Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Bandar Sunway, Subang Jaya, Selangor, 47500, Malaysia. vetris@sunway.edu.my.

Treatment of acute myeloid leukemia models by targeting a cell surface RNA-binding protein

Immunotherapies for acute myeloid leukemia (AML) and other cancers are limited by a lack of tumor-specific targets. Here we discover that RNA-binding proteins and glycosylated RNAs (glycoRNAs) form precisely organized nanodomains on cancer cell surfaces. We characterize nucleophosmin (NPM1) as an abundant cell surface protein (csNPM1) on a variety of tumor types. With a focus on AML, we observe csNPM1 on blasts and leukemic stem cells but not on normal hematopoietic stem cells. We develop a monoclonal antibody to target csNPM1, which exhibits robust anti-tumor activity in multiple syngeneic and xenograft models of AML, including patient-derived xenografts, without observable toxicity. We find that csNPM1 is expressed in a mutation-agnostic manner on primary AML cells and may therefore offer a general strategy for detecting and treating AML. Surface profiling and in vivo work also demonstrate csNPM1 as a target on solid tumors. Our data suggest that csNPM1 and its neighboring glycoRNA-cell surface RNA-binding protein (csRBP) clusters may serve as an alternative antigen class for therapeutic targeting or cell identification.

Author Info: (1) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, US

Author Info: (1) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (2) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. Milner Therapeutics Institute, University of Cambridge, Cambridge, UK. (3) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. Milner Therapeutics Institute, University of Cambridge, Cambridge, UK. (4) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (5) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (6) Department of Physics, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany. (7) Department of Physics, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany. Max Planck Institute for the Science of Light, Erlangen, Germany. (8) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (9) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (10) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (11) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (12) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (13) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (14) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (15) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (16) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (17) Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. (18) Max Planck Institute for the Science of Light, Erlangen, Germany. (19) Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (20) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (21) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (22) Department of Haematology, University of Cambridge, Cambridge, UK. (23) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. (24) Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA. (25) Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA. (26) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Department of Haematology, University of Cambridge, Cambridge, UK. (27) Max Planck Institute for the Science of Light, Erlangen, Germany. Faculty of Medicine 1, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg, Erlangen, Germany. Faculty of Sciences, Department of Physics, Friedrich-Alexander-UniversitŠt Erlangen-NŸrnberg, Erlangen, Germany. (28) Cambridge Institute for Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK. Cambridge Institute of Science, Altos Labs, Cambridge, UK. (29) Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. ryan.flynn@childrens.harvard.edu. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. ryan.flynn@childrens.harvard.edu. Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. ryan.flynn@childrens.harvard.edu. (30) Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. kt404@cam.ac.uk. Department of Haematology, University of Cambridge, Cambridge, UK. kt404@cam.ac.uk. Milner Therapeutics Institute, University of Cambridge, Cambridge, UK. kt404@cam.ac.uk. Wellcome Trust Sanger Institute, Hinxton, UK. kt404@cam.ac.uk.

Glioblastoma Cell Lysate and Adjuvant Nanovaccines via Strategic Vaccination Completely Regress Established Murine Tumors

Tumor vaccines have shown great promise for treating various malignancies; however, glioblastoma (GBM), characterized by its immunosuppressive tumor microenvironment, high heterogeneity, and limited accessibility, has achieved only modest clinical benefits. Here, it is reported that GBM cell lysate nanovaccines boosted with TLR9 agonist CpG ODN (GlioVac) via a strategic vaccination regimen achieve complete regression of malignant murine GBM tumors. Subcutaneous administration of GlioVac promotes uptake by cervical lymph nodes and antigen presentation cells, bolstering antigen cross-presentation and infiltration of GBM-specific CD8(+) T cells into the tumor. Notably, a regimen involving two subcutaneous and three intravenous vaccinations not only activates systemic anti-GBM immunity but also further enhances the tumor infiltration of cytotoxic T lymphocytes, effectively reshaping the "cold" GBM tumor into a "hot" tumor. This approach led to a state of tumor-free survival in 5 out of 7 mice bearing the established GL261 GBM model with complete protection from tumor rechallenge. In an orthotopic hRas-GBM model induced by a lentiviral plasmid, GlioVac resulted in Å100% complete tumor regression. These findings suggest that GlioVac provides a personalized therapeutic vaccine strategy for glioblastoma.

Author Info: (1) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow Univers

Author Info: (1) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China. (2) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China. (3) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China. (4) College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, P. R. China. (5) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China. (6) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China. (7) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China. (8) College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, P. R. China. (9) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China. College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, P. R. China. (10) Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, and State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P. R. China.

A dissolvable microneedle platform for the delivery of tumor-derived total RNA nanovaccines for enhanced tumor immunotherapy

Tumor-derived total RNA (TdRNA) vaccines induce broad immune responses by either synthesizing tumor-specific antigens or activating pattern recognition receptors, making them a promising tool in cancer immunotherapy for the activation of cytotoxic T lymphocytes (CTLs). However, TdRNA vaccines face issues such as low stability and inadequate immune activation. To overcome these challenges, we have developed a dissolvable microneedle delivery platform, PTC NVs@MNs, designed for the simultaneous delivery of TdRNA and CpG oligodeoxynucleotides (CpG ODN). This platform stabilizes TdRNA, maintaining its activity for up to 30 days at room temperature and promotes dendritic cell maturation and then activates T lymphocyte-mediated antitumor immunity through the targeted delivery of TdRNA and CpG. PTC NVs@MNs not only enhance dendritic cell maturation and increase CD8(+) T cell infiltration into tumors, eliciting robust antitumor immune responses that inhibit tumor growth in mice, but also induce antitumor immune memory to prevent tumor development. This innovative approach offers therapeutic and preventive benefits in tumor management. STATEMENT OF SIGNIFICANCE: Tumor-derived total RNA (TdRNA) holds potential for eliciting a broad immune response; however, its therapeutic efficacy against triple-negative breast cancer (TNBC) is constrained by low stability and inadequate immune activation. To overcome these limitations, we engineered a dissolving microneedle patch for transdermal co-delivery of TdRNA and CpG oligodeoxynucleotides (CpG ODN). This system not only stabilizes TdRNA-maintaining its bioactivity for 30 days at room temperature-but also promotes dendritic cell maturation and activates T lymphocyte-mediated antitumor immunity via targeted delivery of both components. This study demonstrated that the well-designed microneedle patch effectively prevents RNA degradation without requiring stringent storage conditions, offering both therapeutic and preventive benefits in tumor management.

Author Info: (1) PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. China. (2) PCFM Lab of Ministry of Education, Sc

Author Info: (1) PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. China. (2) PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. China. (3) PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. China. (4) Nanomedicine Research Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, P. R. China. (5) PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. China. (6) Nanomedicine Research Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, P. R. China. Electronic address: xiaozc5@mail.sysu.edu.cn. (7) PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, P. R. China; Nanomedicine Research Center, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, P. R. China. Electronic address: shuaixt@mail.sysu.edu.cn.

Close Modal

Small change for you. Big change for us!

This Thanksgiving season, show your support for cancer research by donating your change.

In less than a minute, link your credit card with our partner RoundUp App.

Every purchase you make with that card will be rounded up and the change will be donated to ACIR.

All transactions are securely made through Stripe.