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Medical Oncology (Northwood, London,... Jun 2024The immune system plays a pivotal role in the battle against cancer, serving as a formidable guardian in the ongoing fight against malignant cells. To combat these... (Review)
Review
The immune system plays a pivotal role in the battle against cancer, serving as a formidable guardian in the ongoing fight against malignant cells. To combat these malignant cells, immunotherapy has emerged as a prevalent approach leveraging antibodies and peptides such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 to inhibit immune checkpoints and activate T lymphocytes. The optimization of gut microbiota plays a significant role in modulating the defense system in the body. This study explores the potential of certain gut-resident bacteria to amplify the impact of immunotherapy. Contemporary antibiotic treatments, which can impair gut flora, may diminish the efficacy of immune checkpoint blockers. Conversely, probiotics or fecal microbiota transplantation can help re-establish intestinal microflora equilibrium. Additionally, the gut microbiome has been implicated in various strategies to counteract immune resistance, thereby enhancing the success of cancer immunotherapy. This paper also acknowledges cutting-edge technologies such as nanotechnology, CAR-T therapy, ACT therapy, and oncolytic viruses in modulating gut microbiota. Thus, an exhaustive review of literature was performed to uncover the elusive link that could potentiate the gut microbiome's role in augmenting the success of cancer immunotherapy.
Topics: Gastrointestinal Microbiome; Humans; Immunotherapy; Neoplasms; Fecal Microbiota Transplantation; Immune Checkpoint Inhibitors; Probiotics
PubMed: 38874788
DOI: 10.1007/s12032-024-02416-3 -
Mathematical Biosciences and... May 2024Resistance to treatment poses a major challenge for cancer therapy, and oncoviral treatment encounters the issue of viral resistance as well. In this investigation, we...
Resistance to treatment poses a major challenge for cancer therapy, and oncoviral treatment encounters the issue of viral resistance as well. In this investigation, we introduce deterministic differential equation models to explore the effect of resistance on oncolytic viral therapy. Specifically, we classify tumor cells into resistant, sensitive, or infected with respect to oncolytic viruses for our analysis. Immune cells can eliminate both tumor cells and viruses. Our research shows that the introduction of immune cells into the tumor-virus interaction prevents all tumor cells from becoming resistant in the absence of conversion from resistance to sensitivity, given that the proliferation rate of immune cells exceeds their death rate. The inclusion of immune cells leads to an additional virus-free equilibrium when the immune cell recruitment rate is sufficiently high. The total tumor burden at this virus-free equilibrium is smaller than that at the virus-free and immune-free equilibrium. Therefore, immune cells are capable of reducing the tumor load under the condition of sufficient immune strength. Numerical investigations reveal that the virus transmission rate and parameters related to the immune response significantly impact treatment outcomes. However, monotherapy alone is insufficient for eradicating tumor cells, necessitating the implementation of additional therapies. Further numerical simulation shows that combination therapy with chimeric antigen receptor (CAR T-cell) therapy can enhance the success of treatment.
Topics: Oncolytic Virotherapy; Humans; Neoplasms; Oncolytic Viruses; Computer Simulation; Animals; Tumor Burden; Cell Proliferation
PubMed: 38872564
DOI: 10.3934/mbe.2024261 -
PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway.The Journal of Experimental Medicine Jul 2024While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic...
While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 promoted a metabolic shift characterized by enhanced glycolysis rate that resulted in increased lactate production. In turn, lactate inhibited type I IFN responses. In addition to adding mechanistic insight into PD-L1 intrinsic function, our results will also help guide the numerous ongoing efforts to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.
Topics: Animals; Female; Humans; Mice; B7-H1 Antigen; Cell Line, Tumor; Glycolysis; Interferon Type I; Lactic Acid; Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; Signal Transduction; Male
PubMed: 38869480
DOI: 10.1084/jem.20221721 -
Stem Cells Translational Medicine Jun 2024Oncolytic adenoviruses have emerged as a promising therapeutic approach for cancer therapy. However, systemic delivery of the viruses to metastatic tumors remains a...
Oncolytic adenoviruses have emerged as a promising therapeutic approach for cancer therapy. However, systemic delivery of the viruses to metastatic tumors remains a major challenge. Mesenchymal stem cells (MSCs) possess tumor tropism property and can be used as cellular vehicles for delivering oncolytic adenoviruses to tumor sites. Since telomerase activity is found in ~90% of human carcinomas, but undetected in normal adult cells, the human telomerase reverse transcriptase gene (TERT) promoter can be exploited for regulating the replication of oncolytic adenoviruses. Here, we evaluated the antitumor effects of syngeneic murine MSCs loaded with the luciferase-expressing, telomerase-dependent oncolytic adenovirus Ad.GS2 (MSC-Ad.GS2) and Ad.GS2 alone on metastatic MBT-2 bladder tumors. MSCs supported a low degree of Ad.GS2 replication, which could be augmented by coculture with MBT-2 cells or tumor-conditioned medium (TCM), suggesting that viral replication is increased when MSC-Ad.GS2 migrates to tumor sites. MBT-2 cells and TCM enhanced viral replication in Ad.GS2-infected MSCs. SDF-1 is a stem cell homing factor. Our results suggest that the SDF-1/STAT3/TERT signaling axis in MSCs in response to the tumor microenvironment may contribute to the enhanced replication of Ad.GS2 carried by MSCs. Notably, we demonstrate the potent therapeutic efficacy of systemically delivered MSC-Ad.GS2 in pleural disseminated tumor and experimental metastasis models using intrapleural and tail vein injection of MBT-2 cells, respectively. Treatment with MSC-Ad.GS2 significantly reduced tumor growth and prolonged the survival of mice bearing metastatic bladder tumors. Since telomerase is expressed in a broad spectrum of cancers, this therapeutic strategy may be broadly applicable.
PubMed: 38864209
DOI: 10.1093/stcltm/szae039 -
IET Nanobiotechnology 2024Pancreatic cancer is a leading cause of cancer-related deaths worldwide. Conventional therapies often provide limited success, necessitating the need for novel...
Pancreatic cancer is a leading cause of cancer-related deaths worldwide. Conventional therapies often provide limited success, necessitating the need for novel therapeutic strategies. Oncolytic viruses (OVs) are a class of viruses that specifically target and kill cancer cells while leaving normal cells unharmed. These viruses have shown promise in the treatment of various cancers, including pancreatic cancer. However, their use in clinical settings has been limited by several factors. Their inability to efficiently infect and kill tumor cells. To overcome this limitation, a cell membrane-coated oncolytic virus was developed. However, the necessity of homologous and nonhomologous tumor cell membranes for their function has not yet been proven. This novel virus displayed increased infectivity and killing activity against tumor cells compared to nonhomologous tumor cell membranes and noncoated viruses. We believe that the homologous tumor cell membranes-coated OVs can enhance the therapeutic potential for pancreatic cancer therapy.
Topics: Pancreatic Neoplasms; Humans; Oncolytic Virotherapy; Cell Membrane; Oncolytic Viruses; Cell Line, Tumor; Animals
PubMed: 38863971
DOI: 10.1049/2024/9970665 -
Cell Biochemistry and Function Jun 2024The heterogeneity of the solid tumor microenvironment (TME) impairs the therapeutic efficacy of standard therapies and also reduces the infiltration of antitumor immune... (Review)
Review
The heterogeneity of the solid tumor microenvironment (TME) impairs the therapeutic efficacy of standard therapies and also reduces the infiltration of antitumor immune cells, all of which lead to tumor progression and invasion. In addition, self-renewing cancer stem cells (CSCs) support tumor dormancy, drug resistance, and recurrence, all of which might pose challenges to the eradication of malignant tumor masses with current therapies. Natural forms of oncolytic viruses (OVs) or engineered OVs are known for their potential to directly target and kill tumor cells or indirectly eradicate tumor cells by involving antitumor immune responses, including enhancement of infiltrating antitumor immune cells, induction of immunogenic cell death, and reprogramming of cold TME to an immune-sensitive hot state. More importantly, OVs can target stemness factors that promote tumor progression, which subsequently enhances the efficacy of immunotherapies targeting solid tumors, particularly the CSC subpopulation. Herein, we describe the role of CSCs in tumor heterogeneity and resistance and then highlight the potential and remaining challenges of immunotherapies targeting CSCs. We then review the potential of OVs to improve tumor immunogenicity and target CSCsĀ and finally summarize the challenges within the therapeutic application of OVs in preclinical and clinical trials.
Topics: Humans; Neoplastic Stem Cells; Oncolytic Viruses; Immunotherapy; Neoplasms; Oncolytic Virotherapy; Tumor Microenvironment; Animals
PubMed: 38856033
DOI: 10.1002/cbf.4055 -
Chinese Medical Journal Jun 2024Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Its high recurrence rate and lack of effective control drugs result in a 5-year...
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Its high recurrence rate and lack of effective control drugs result in a 5-year survival rate of only about 10%. HCC is a tumor regulated by the immune system. Significant breakthroughs have occurred in treating solid tumors with immunotherapy in recent years. Various immunotherapies, such as immune checkpoint inhibitors (ICIs), including combination therapies, have demonstrated promising therapeutic effects in both clinical applications and research. Other immunotherapies, such as adoptive cell therapies and oncolytic viruses, are also emerging, offering hope for addressing long-term survival issues in HCC. This article reviews current commonly used immunotherapy strategies and the latest research findings for reference.
PubMed: 38855876
DOI: 10.1097/CM9.0000000000003060 -
Scientific Reports Jun 2024LHPP has been shown to be a new tumor suppressor, and has a tendency to be under-expressed in a variety of cancers. Oncolytic virotheray is a promising therapeutics for...
LHPP has been shown to be a new tumor suppressor, and has a tendency to be under-expressed in a variety of cancers. Oncolytic virotheray is a promising therapeutics for lung cancer in recent decade years. Here we successfully constructed a new recombinant oncolytic adenovirus GD55-LHPP and investigated the effect of GD55-LHPP on the growth of lung cancer cells in vitro and in vivo. The results showed that LHPP had lower expression in either lung cancer cells or clinical lung cancer tissues compared with normal cells or tissues, and GD55-LHPP effectively mediated LHPP expression in lung cancer cells. GD55-LHPP could effectively inhibit the proliferation of lung cancer cell lines and rarely affected normal cell growth. Mechanically, the oncolytic adenovirus GD55-LHPP was able to induce stronger apoptosis of lung cancer cells compared with GD55 through the activation of caspase signal pathway. Notably, GD55-LHPP also activated autophagy-related signal pathway. Further, GD55-LHPP efficiently inhibited tumor growth in lung cancer xenograft in mice and prolonged animal survival rate compared with the control GD55 or PBS. In conclusion, the novel construct GD55-LHPP provides a valuable strategy for lung cancer-targeted therapy and develop the role of tumor suppress gene LHPP in lung cancer gene therapy.
Topics: Lung Neoplasms; Humans; Animals; Oncolytic Virotherapy; Adenoviridae; Oncolytic Viruses; Mice; Cell Line, Tumor; Xenograft Model Antitumor Assays; Apoptosis; Cell Proliferation; Mice, Nude; Female; Autophagy
PubMed: 38849383
DOI: 10.1038/s41598-024-63325-z -
Molecular Therapy. Oncology Jun 2024Oncolytic virotherapy represents a promising approach in cancer immunotherapy. The primary delivery method for oncolytic viruses (OVs) is intratumoral injection, which... (Review)
Review
Oncolytic virotherapy represents a promising approach in cancer immunotherapy. The primary delivery method for oncolytic viruses (OVs) is intratumoral injection, which apparently limits their clinical application. For patients with advanced cancer with disseminated metastasis, systemic administration is considered the optimal approach. However, the direct delivery of naked viruses through intravenous injection presents challenges, including rapid clearance by the immune system, inadequate accumulation in tumors, and significant side effects. Consequently, the development of drug delivery strategies has led to the emergence of various bio-materials serving as viral vectors, thereby improving the anti-tumor efficacy of oncolytic virotherapy. This review provides an overview of innovative strategies for delivering OVs, with a focus on nanoparticle-based or cell-based delivery systems. Recent pre-clinical and clinical studies are examined to highlight the enhanced efficacy of systemic delivery using these novel platforms. In addition, prevalent challenges in current research are briefly discussed, and potential solutions are proposed.
PubMed: 38845744
DOI: 10.1016/j.omton.2024.200809 -
Cancer Gene Therapy Jun 2024Systems biology has been applied at the multi-scale level within the cancer field, improving cancer prevention, diagnosis and enabling precision medicine approaches....
Systems biology has been applied at the multi-scale level within the cancer field, improving cancer prevention, diagnosis and enabling precision medicine approaches. While systems biology can expand the knowledge and skills for oncological treatment, it also represents a challenging expedition due to cancer complexity, heterogeneity and diversity not only between different cancer indications, but also in its evolution process through space and time. Here, by characterizing the transcriptional perturbations of the tumor microenvironment induced by oncolytic, we aimed to rationally design a novel armed oncolytic herpes virus. We found that intratumor oncovirotherapy with HSV-1 induces T-cell activation signatures and transcriptionally activates several costimulatory molecules. We identified differentially expressed costimulatory receptors and binding partners, where inducible co-stimulators (ICOS) resulted in the potentially most beneficial targeted therapy. Through an ex-vivo transcriptomic analysis, we explored the potential of arming an oncolytic virus as a combination therapy strategy; in particular, we engineered a targeted herpes virus encoding ICOSL (THV_ICOSL), which resulted in a significant improvement in tumor size control compared to unarmed parental virus. Also, combination with a PD-1 inhibitor enhanced antitumor efficacy as predictable by upregulation of PD-1 and ligands pair (PD-L1/PD-L2) upon oncolytic virus injection. Generation of the human version of this virus encoding hICOSL orthologue effectively and specifically activated human T cells by triggering the ICOS pathway. Our data support the data-driven generation of armed oncolytic viruses as combination immunotherapeutic with checkpoint inhibitors.
PubMed: 38839891
DOI: 10.1038/s41417-024-00790-8