RESUMO
Immunotherapy has emerged as a promising approach for cancer treatment, with oncolytic adenoviruses showing power as immunotherapeutic agents. In this study, we investigated the immunotherapeutic potential of an adenovirus construct expressing CXCL9, CXCL10, or IL-15 in clear cell renal cell carcinoma (ccRCC) tumor models. Our results demonstrated robust cytokine secretion upon viral treatment, suggesting effective transgene expression. Subsequent analysis using resistance-based transwell migration and microfluidic chip assays demonstrated increased T-cell migration in response to chemokine secretion by infected cells in both 2D and 3D cell models. Flow cytometry analysis revealed CXCR3 receptor expression across T-cell subsets, with the highest percentage found on CD8+ T-cells, underscoring their key role in immune cell migration. Alongside T-cells, we also detected NK-cells in the tumors of immunocompromised mice treated with cytokine-encoding adenoviruses. Furthermore, we identified potential immunogenic antigens that may enhance the efficacy and specificity of our armed oncolytic adenoviruses in ccRCC. Overall, our findings using ccRCC cell line, in vivo humanized mice, physiologically relevant PDCs in 2D and patient-derived organoids (PDOs) in 3D suggest that chemokine-armed adenoviruses hold promise for enhancing T-cell migration and improving immunotherapy outcomes in ccRCC. Our study contributes to the development of more effective ccRCC treatment strategies by elucidating immune cell infiltration and activation mechanisms within the tumor microenvironment (TME) and highlights the usefulness of PDOs for predicting clinical relevance and validating novel immunotherapeutic approaches. Overall, our research offers insights into the rational design and optimization of viral-based immunotherapies for ccRCC.
Assuntos
Adenoviridae , Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/genética , Humanos , Animais , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Neoplasias Renais/patologia , Neoplasias Renais/genética , Camundongos , Adenoviridae/genética , Adenoviridae/imunologia , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Terapia Viral Oncolítica/métodos , Imunoterapia/métodos , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Quimiocina CXCL9/imunologia , Movimento Celular , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL10/imunologia , Citocinas/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Interleucina-15/genética , Interleucina-15/metabolismo , Interleucina-15/imunologia , Receptores CXCR3/metabolismo , Receptores CXCR3/genética , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Linfócitos T CD8-Positivos/imunologiaRESUMO
BACKGROUND: Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults with the lowest survival rates five years post-diagnosis. Oncolytic viruses (OVs) selectively target and damage cancer cells, and for this reason they are being investigated as new therapeutic tools also against GBM. METHODS: An oncolytic herpes simplex virus type 1 (oHSV-1) with deletions in the γ34.5 neurovirulence gene and the US12 gene, expressing enhanced green fluorescent protein (EGFP-oHSV-1) as reporter gene was generated and tested for its capacity to infect and kill the murine GL261 glioblastoma (GBM) cell line. Syngeneic mice were orthotopically injected with GL261cells. Seven days post-implantation, EGFP-oHSV-1 was administered intratumorally. Twenty-one days after parental tumor challenge in the opposite brain hemisphere, mice were sacrified and their brains were analysed by immunohistochemistry to assess tumor presence and cell infiltrate. RESULTS: oHSV-1 replicates and induces cell death of GL261 cells in vitro. A single intracranial injection of EGFP-oHSV-1 in established GL261 tumors significantly prolongs survival in all treated mice compared to placebo treatment. Notably, 45% of treated mice became long-term survivors, and rejected GL261 cells upon rechallenge in the contralateral brain hemisphere, indicating an anamnestic antitumoral immune response. Post-mortem analysis revealed a profound modification of the tumor microenvironment with increased infiltration of CD4 + and CD8 + T lymphocytes, intertumoral vascular collapse and activation and redistribution of macrophage, microglia, and astroglia in the tumor area, with the formation of intense fibrotic tissue suggestive of complete rejection in long-term survivor mice. CONCLUSIONS: EGFP-oHSV1 demonstrates potent antitumoral activity in an immunocompetent GBM model as a monotherapy, resulting from direct cell killing combined with the stimulation of a protective adaptive immune response. These results open the way to possible application of our strategy in clinical setting.
Assuntos
Imunidade Adaptativa , Glioblastoma , Herpesvirus Humano 1 , Terapia Viral Oncolítica , Animais , Glioblastoma/terapia , Glioblastoma/imunologia , Glioblastoma/patologia , Linhagem Celular Tumoral , Terapia Viral Oncolítica/métodos , Vetores Genéticos , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patologia , Vírus Oncolíticos/genética , Camundongos Endogâmicos C57BL , Proteínas de Fluorescência Verde/metabolismo , Camundongos , HumanosRESUMO
Pancreatic cancer presents formidable challenges due to rapid progression and resistance to conventional treatments. Oncolytic viruses (OVs) selectively infect cancer cells and cause cancer cells to lyse, releasing molecules that can be identified by the host's immune system. Moreover, OV can carry immune-stimulatory payloads such as interleukin-12, which when delivered locally can enhance immune system-mediated tumor killing. OVs are very well tolerated by cancer patients due to their ability to selectively target tumors without affecting surrounding normal tissues. OVs have recently been combined with other therapies, including chemotherapy and immunotherapy, to improve clinical outcomes. Several OVs including adenovirus, herpes simplex viruses (HSVs), vaccinia virus, parvovirus, reovirus, and measles virus have been evaluated in preclinical and clinical settings for the treatment of pancreatic cancer. We evaluated the safety and tolerability of a replication-competent oncolytic adenoviral vector carrying two suicide genes (thymidine kinase, TK; and cytosine deaminase, CD) and human interleukin-12 (hIL12) in metastatic pancreatic cancer patients in a phase 1 trial. This vector was found to be safe and well-tolerated at the highest doses tested without causing any significant adverse events (SAEs). Moreover, long-term follow-up studies indicated an increase in the overall survival (OS) in subjects receiving the highest dose of the OV. Our encouraging long-term survival data provide hope for patients with advanced pancreatic cancer, a disease that has not seen a meaningful increase in OS in the last five decades. In this review article, we highlight several preclinical and clinical studies and discuss future directions for optimizing OV therapy in pancreatic cancer. We envision OV-based gene therapy to be a game changer in the near future with the advent of newer generation OVs that have higher specificity and selectivity combined with personalized treatment plans developed under AI guidance.
Assuntos
Terapia Viral Oncolítica , Vírus Oncolíticos , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/imunologia , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Terapia Viral Oncolítica/métodos , Animais , Imunoterapia/métodos , Vetores Genéticos/genética , Vetores Genéticos/administração & dosagem , Interleucina-12/genética , Terapia CombinadaRESUMO
ICVB-1042 is an oncolytic adenovirus containing modifications to enhance replication, lysis, and viral spreading in tumor cells. The anti-tumor activity, immune activation, tropism, selectivity, and mechanism of action were evaluated in preparation for a first-in-human study. ICVB-1042 was at least 100-fold more cytotoxic in A549 cells than in normal primary cells tested, demonstrating its high tumor selectivity and a low likelihood of targeting primary tissues. ICVB-1042 administered to mice intravenously or intratumorally was effective in reducing tumor burden. Its intravenous administration also inhibited tumor growth in orthotopic models. ICVB-1042 was well tolerated in mice compared to HAdV-C5 (Wt Ad5), with reduced liver sequestration, supporting safety of the drug for systemic delivery. These preclinical data demonstrating the safety and potency of ICVB-1042 for treatment of various solid tumors support the ongoing clinical investigation (NCT05904236).
Assuntos
Adenoviridae , Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Humanos , Terapia Viral Oncolítica/métodos , Camundongos , Vírus Oncolíticos/genética , Neoplasias/terapia , Adenoviridae/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino , Linhagem Celular Tumoral , Células A549 , Replicação Viral , Camundongos NusRESUMO
BACKGROUND: The therapeutic potential of oncolytic measles virotherapy has been demonstrated across various malignancies. However, the effectiveness against human breast cancer (BC) and the underlying mechanisms of the recombinant measles virus vaccine strain Hu191 (rMeV-Hu191) remain unclear. METHODS: We utilized a range of methods, including cell viability assay, Western blot, flow cytometry, immunofluorescence, SA-ß-gal staining, reverse transcription quantitative real-time PCR, transcriptome sequencing, BC xenograft mouse models, and immunohistochemistry to evaluate the antitumor efficacy of rMeV-Hu191 against BC and elucidate the underlying mechanism. Additionally, we employed transcriptomics and gene set enrichment analysis to analyze the lipid metabolism status of BC cells following rMeV-Hu191 infection. RESULTS: Our study revealed the multifaceted antitumor effects of rMeV-Hu191 against BC. rMeV-Hu191 induced apoptosis, inhibited proliferation, and promoted senescence in BC cells. Furthermore, rMeV-Hu191 was associated with changes in oxidative stress and lipid homeostasis in infected BC cells. In vivo, studies using a BC xenograft mouse model confirmed a significant reduction in tumor growth following local injection of rMeV-Hu191. CONCLUSIONS: The findings highlight the potential of rMeV-Hu191 as a promising treatment for BC and provide valuable insights into the mechanisms underlying its oncolytic effect.
Assuntos
Neoplasias da Mama , Vírus do Sarampo , Terapia Viral Oncolítica , Animais , Neoplasias da Mama/terapia , Neoplasias da Mama/genética , Humanos , Camundongos , Feminino , Terapia Viral Oncolítica/métodos , Linhagem Celular Tumoral , Vírus do Sarampo/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Apoptose , Proliferação de Células , Vacina contra Sarampo , Vírus Oncolíticos/genética , Sobrevivência CelularRESUMO
Oncolytic viruses (OVs) are promising cancer immunotherapy agents that stimulate anti-tumor immunity through the preferential infection and killing of tumor cells. OVs are currently under limited clinical usage, due in part to their restricted efficacy as monotherapies. Current efforts for enhancement of the therapeutic potency of OVs involve their combination with other therapy modalities, aiming at the concomitant exploitation of complementary tumor weaknesses. In this context, microtubule-targeting agents (MTAs) pose as an enticing option, as they perturb microtubule dynamics and function, induce cell-cycle arrest, and cause mitotic cell death. MTAs induce therapeutic benefit through cancer-cell-autonomous and non-cell-autonomous mechanisms and are a main component of the standard of care for different malignancies. However, off-target effects and acquired resistance involving distinct cellular and molecular mechanisms may limit the overall efficacy of MTA-based therapy. When combined, OVs and MTAs may enhance therapeutic efficacy through increases in OV infection and immunogenic cell death and a decreased probability of acquired resistance. In this review, we introduce OVs and MTAs, describe molecular features of their activity in cancer cells, and discuss studies and clinical trials in which the combination has been tested.
Assuntos
Microtúbulos , Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Terapia Viral Oncolítica/métodos , Neoplasias/terapia , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Vírus Oncolíticos/genética , Animais , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/uso terapêutico , Imunoterapia/métodos , Terapia CombinadaRESUMO
Lung cancer remains a formidable health challenge due to its high mortality and morbidity rates. Non-small cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancer cases, with small cell lung cancer (SCLC) accounting for the remainder. Both NSCLC and SCLC cells express receptor tyrosine kinases, which may be overexpressed or mutated in lung cancer, leading to increased activation. The c-Met receptor tyrosine kinase, crucial for cell transformation and tumor growth, invasion, and metastasis, became the focus of our study. We used an E1B55KD-deleted, replication-selective oncolytic adenovirus (Ad.What), driven by the c-Met promoter, targeting lung cancer cells with c-Met overexpression, thus sparing normal cells. Previous studies have shown the enhanced antitumor efficacy of oncolytic adenoviruses when combined with chemotherapeutic agents. We explored combining rapamycin, a selective mTOR inhibitor with promising clinical trial outcomes for various cancers, with Ad.What. This combination increased infectivity by augmenting the expression of coxsackievirus and adenovirus receptors and αV integrin on cancer cells and induced autophagy. Our findings suggest that combining a c-Met promoter-driven oncolytic adenovirus with rapamycin could be an effective lung cancer treatment strategy, offering a targeted approach to exploit lung cancer cells' vulnerabilities, potentially marking a significant advancement in managing this deadly disease.
Assuntos
Adenoviridae , Neoplasias Pulmonares , Terapia Viral Oncolítica , Vírus Oncolíticos , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-met , Sirolimo , Humanos , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patologia , Regiões Promotoras Genéticas/genética , Adenoviridae/genética , Linhagem Celular Tumoral , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Animais , Camundongos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologiaRESUMO
Newcastle disease virus (NDV) is a highly pathogenic avian infectious disease agent and also a promising oncolytic virus with broad application prospects. The Endosomal Sorting Complex Required for Transport (ESCRT) machinery has been increasingly recognized for its crucial role in the life cycles of enveloped viruses, influencing processes such as viral entry, replication, and budding. In this study, we employed an RNA interference screening approach to identify key ESCRT components that regulate NDV replication in tumor cells. qPCR, immunofluorescence, and Western blot assays demonstrated that knockdown of HRS, CHMP4A, CHMP4B, and CHMP4C significantly impaired NDV replication in HeLa cells, with HRS exhibiting the most pronounced inhibitory effect. Additionally, HRS knockout significantly inhibited viral budding and suppressed NDV-induced cell death in HeLa cells. Notably, NDV infection was shown to significantly upregulate HRS gene and protein expression in a time-dependent manner. In conclusion, this study systematically identifies critical ESCRT components involved in NDV replication within tumor cells, with a particular focus on the role of HRS in promoting NDV's replication by promoting viral budding, offering new insights for the development of NDV-based oncolytic therapies.
Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte , Vírus da Doença de Newcastle , Liberação de Vírus , Replicação Viral , Vírus da Doença de Newcastle/fisiologia , Vírus da Doença de Newcastle/genética , Humanos , Células HeLa , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Vírus Oncolíticos/fisiologia , Vírus Oncolíticos/genética , AnimaisRESUMO
Colorectal cancer (CRC) is the second common cause of cancer mortality worldwide, and it still lacks effective approaches for relapsed and metastatic CRC. Recently, oncolytic virus has been emerged as a promising immune therapeutic strategy. In this study, we develop a novel oncolytic adenovirus, rAd.mDCN.mCD40L, which drive oncolytic activity by telomerase reverse transcriptase promoter (TERTp). rAd.mDCN.mCD40L expressed both mouse genes of decorin (mDCN) and CD40 ligand (mCD40L), and produced effective cytotoxicity in both human and mouse CRC cells. Moreover, oncolytic adenovirus mediated mDCN over-expression inhibited Met expression in vitro. In CT26 subcutaneous tumor model, intratumorally delivery of oncolytic adenoviruses could inhibit tumor growth and liver metastasis, while mDCN and/or mCD40L armed oncolytic adenoviruses produced much more impressive responses. No obvious toxicity was detected in lung, liver and spleen. Moreover, mDCN and/or mCD40L armed oncolytic adenoviruses altered the immune state to activate anti-tumor responses, including increasing CD8+ T effector cells and CD4+ memory T cells, reducing MDSCs and Tregs in peripheral blood. Furthermore, mDCN and/or mCD40L armed oncolytic adenoviruses mediated mDCN and/or mCD40L expression in tumors, and up-regulated Th1 cytokines and reduced Th2 cytokines in tumors, which will be benefit for remodeling tumor microenvironment. Importantly, rAd.mDCN.mCD40L and rAd.mCD40L prevented tumor liver metastasis much more effectively than rAd.Null and rAd.mDCN. Therefore, rAd.mDCN.mCD40L and rAd.mCD40L are promising approaches for CRC therapy.
Assuntos
Adenoviridae , Ligante de CD40 , Neoplasias Colorretais , Decorina , Neoplasias Hepáticas , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Neoplasias Colorretais/terapia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/genética , Decorina/genética , Decorina/metabolismo , Adenoviridae/genética , Humanos , Camundongos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/genética , Ligante de CD40/genética , Ligante de CD40/metabolismo , Ligante de CD40/imunologia , Terapia Viral Oncolítica/métodos , Linhagem Celular Tumoral , Vírus Oncolíticos/genética , Camundongos Endogâmicos BALB C , Modelos Animais de DoençasRESUMO
Targeted antineoplastic immunotherapies have achieved remarkable clinical outcomes. However, resistance to these therapies due to target absence or antigen shedding limits their efficacy and excludes tumours from candidacy. To address this limitation, here we engineer an oncolytic rhabdovirus, vesicular stomatitis virus (VSVΔ51), to express a truncated targeted antigen, which allows for HER2-targeting with trastuzumab. The truncated HER2 (HER2T) lacks signaling capabilities and is efficiently expressed on infected cell surfaces. VSVΔ51-mediated HER2T expression simulates HER2-positive status in tumours, enabling effective treatment with the antibody-drug conjugate trastuzumab emtansine in vitro, ex vivo, and in vivo. Additionally, we combine VSVΔ51-HER2T with an oncolytic vaccinia virus expressing a HER2-targeted T-cell engager. This dual-virus therapeutic strategy demonstrates potent curative efficacy in vivo in female mice using CD3+ infiltrate for anti-tumour immunity. Our findings showcase the ability to tailor the tumour microenvironment using oncolytic viruses, thereby enhancing compatibility with "off-the-shelf" targeted therapies.
Assuntos
Imunoterapia , Terapia Viral Oncolítica , Vírus Oncolíticos , Receptor ErbB-2 , Linfócitos T , Trastuzumab , Vaccinia virus , Animais , Feminino , Humanos , Imunoterapia/métodos , Camundongos , Receptor ErbB-2/metabolismo , Receptor ErbB-2/imunologia , Receptor ErbB-2/genética , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Linfócitos T/imunologia , Linhagem Celular Tumoral , Vaccinia virus/genética , Vaccinia virus/imunologia , Trastuzumab/uso terapêutico , Trastuzumab/farmacologia , Microambiente Tumoral/imunologia , Vesiculovirus/genética , Vesiculovirus/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB CRESUMO
Rhabdoviral vectors can induce lysis of cancer cells. While studied almost exclusively at 37 °C, viruses are subject to a range of temperatures in vivo, including temperatures ≤31 °C. Despite potential implications, the effect of temperatures <37 °C on the performance of rhabdoviral vectors is unknown. We investigated the effect of low anatomical temperatures on two rhabdoviruses, vesicular stomatitis virus (VSV) and Maraba virus (MG1). Using a metabolic resazurin assay, VSV- and MG1-mediated oncolysis was characterized in a panel of cell lines at 28, 31, 34 and 37 °C. The oncolytic ability of both viruses was hindered at 31 and 28 °C. Cold adaptation of both viruses was attempted as a mitigation strategy. Viruses were serially passaged at decreasing temperatures in an attempt to induce mutations. Unfortunately, the cold-adaptation strategies failed to potentiate the oncolytic activity of the viruses at temperatures <37 °C. Interestingly, we discovered that viral replication was unaffected at low temperatures despite the abrogation of oncolytic activity. In contrast, the proliferation of cancer cells was reduced at low temperatures. Equivalent oncolytic effects could be achieved if cells at low temperatures were treated with viruses for longer times. This suggests that rhabdovirus-mediated oncolysis could be compromised at low temperatures in vivo where therapeutic windows are limited.
Assuntos
Temperatura Baixa , Vírus Oncolíticos , Rhabdoviridae , Replicação Viral , Humanos , Rhabdoviridae/fisiologia , Rhabdoviridae/genética , Animais , Vírus Oncolíticos/fisiologia , Vírus Oncolíticos/genética , Vesiculovirus/fisiologia , Vesiculovirus/genética , Terapia Viral Oncolítica/métodos , Linhagem Celular , Vetores Genéticos/genética , Linhagem Celular Tumoral , TemperaturaAssuntos
Adenoviridae , Interleucina-2 , Terapia Viral Oncolítica , Vírus Oncolíticos , Neoplasias Ovarianas , Humanos , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/genética , Feminino , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Adenoviridae/genética , Interleucina-2/genética , Interleucina-2/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linhagem Celular Tumoral , Animais , Vetores Genéticos/genética , Vetores Genéticos/administração & dosagem , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto , Terapia Genética/métodosRESUMO
Oncolytic viruses (OV) are a promising strategy in cancer immunotherapy. Their capacity to promote anti-tumoral immunity locally raises hope that cancers unresponsive to current immunotherapy approaches could be tackled more efficiently. In this context, tumor-associated macrophages (TAM) must be considered because of their pivotal role in cancer immunity. Even though TAM tend to inhibit anti-tumoral responses, their ability to secrete pro-inflammatory cytokines and phagocytose cancer cells can be harnessed to promote therapeutic cancer immunity. OVs have the potential to promote TAM pro-inflammatory functions that favor anti-tumoral immunity. But in parallel, TAM pro-inflammatory functions induce OV clearance in the tumor, thereby limiting OV efficacy and highlighting that the interaction between OV and TAM is a double edge sword. Moreover, engineered OVs were recently developed to modulate specific TAM functions such as phagocytic activity. The potential of circulating monocytes to deliver OV into the tumor after intravenous administration is also emerging. In this review, we will present the interaction between OV and TAM, the potential of engineered OV to modulate specific TAM functions, and the promising role of circulating monocytes in OV delivery to the tumor.
Assuntos
Imunoterapia , Neoplasias , Terapia Viral Oncolítica , Vírus Oncolíticos , Macrófagos Associados a Tumor , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Vírus Oncolíticos/genética , Vírus Oncolíticos/imunologia , Imunoterapia/métodos , Terapia Viral Oncolítica/métodos , Macrófagos Associados a Tumor/imunologia , AnimaisRESUMO
Inflammatory myofibroblastic tumor (IMT) is a rare pathological entity first described in 1939. This lesion is most commonly found in the lungs, but cases involving other systems, such as the central nervous system known as intracranial IMT (IIMT), have also been reported. Diagnosis currently relies on pathological results due to the lack of characteristic imaging changes. Surgical resection is an effective treatment, though the disease is invasive and may recur. Previous literature has reported a high level of programmed death 1 (PD-1) expression in IMT tissues, suggesting that immunotherapy may be effective for this condition. In this case report, we present a middle-aged male who received PD-1 inhibitor and oncolytic adenovirus (Ad-TD-nsIL12) treatment after IIMT resection surgery. This successful approach provides a new direction for the treatment of IIMT.
Assuntos
Adenoviridae , Neoplasias Encefálicas , Inibidores de Checkpoint Imunológico , Terapia Viral Oncolítica , Humanos , Masculino , Terapia Viral Oncolítica/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Encefálicas/terapia , Pessoa de Meia-Idade , Adenoviridae/genética , Vírus Oncolíticos/genética , Antígeno B7-H1/antagonistas & inibidores , Neoplasias de Tecido Muscular/terapia , Terapia Combinada , Resultado do TratamentoRESUMO
Oncolytic viruses and morbilliviruses in particular, represent an interesting therapeutic approach for tumors with a poor prognosis and frequent resistance to conventional therapies. Canine histiocytic sarcomas (HS) exemplify such a neoplasm in need for new curative approaches. Previous investigations demonstrated a limited success of an acute intratumoral application of canine distemper virus (CDV) on xenotransplanted canine histiocytic sarcoma cells (DH82 cells), while persistently CDV-infected DH82 cell transplants exhibited a complete spontaneous regression. Therefore, the present study focuses on an intratumoral application of persistently CDV vaccine strain Onderstepoort-infected DH82 (DH82 Ond p.i.) cells into non-infected subcutaneous DH82 cell transplants in a murine model. DH82 cell transplants that received 10 applications, two days apart, showed a transient growth retardation as well as larger areas of intratumoral necrosis, lower mitotic rates, and a decreased intratumoral vascularization compared to controls. Viral mRNA was detected in all neoplasms following application of DH82 Ond p.i. cells until 66 days after the last injection. Furthermore, infectious virus was present until 62 days after the last injection. Although complete regression was not achieved, the present application regimen provides promising results as a basis for further treatments, particularly with genetically modified viruses, to enhance the observed effects.
Assuntos
Vírus da Cinomose Canina , Sarcoma Histiocítico , Terapia Viral Oncolítica , Animais , Vírus da Cinomose Canina/patogenicidade , Vírus da Cinomose Canina/genética , Cães , Sarcoma Histiocítico/virologia , Camundongos , Terapia Viral Oncolítica/métodos , Linhagem Celular Tumoral , Cinomose/virologia , Vírus Oncolíticos/genética , Vírus Oncolíticos/fisiologiaRESUMO
Oncolytic viruses combined with immunotherapy offer significant potential in tumor therapy. In this study, we engineered a further attenuated pseudorabies virus (PRV) vaccine strain that incorporates a PD-L1 inhibitor and demonstrated its promise as an oncolytic virus in tumor therapy. We first showed that the naturally attenuated PRV vaccine strain Bartha can efficiently infect tumor cells from multiple species, including humans, mice, and dogs in vitro. We then evaluated the safety and anti-tumor efficacy of this vaccine strain and its different single-gene deletion mutants using the B16-F10 melanoma mouse model. The TK deletion strain emerged as the optimal vector, and we inserted a PD-L1 inhibitor (iPD-L1) into it using CRISPR/Cas9 technology. Compared with the control, the recombinant PRV (rPRV-iPD-L1) exhibited more dramatic anti-tumor effects in the B16-F10 melanoma mouse model. Our study suggests that PRV can be developed not only as an oncolytic virus but also a powerful vector for expressing foreign genes to modulate the tumor microenvironment.
Assuntos
Antígeno B7-H1 , Herpesvirus Suídeo 1 , Melanoma Experimental , Terapia Viral Oncolítica , Vírus Oncolíticos , Animais , Camundongos , Vírus Oncolíticos/genética , Herpesvirus Suídeo 1/genética , Herpesvirus Suídeo 1/fisiologia , Terapia Viral Oncolítica/métodos , Melanoma Experimental/terapia , Humanos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Feminino , Cães , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Vetores Genéticos/genética , Imunoterapia/métodos , Microambiente TumoralRESUMO
Introduction: Malignant peripheral nerve sheath tumors (MPNST) pose a significant therapeutic challenge due to high recurrence rates after surgical resection and a largely ineffective response to traditional chemotherapy. An alternative treatment strategy is oncolytic viroimmunotherapy, which can elicit a durable and systemic antitumor immune response and is Food and Drug Administration (FDA)-approved for the treatment of melanoma. Unfortunately, only a subset of patients responds completely, underscoring the need to address barriers hindering viroimmunotherapy effectiveness. Methods: Here we investigated the therapeutic utility of targeting key components of the MPNST immunosuppressive microenvironment to enhance viroimmunotherapy's antitumor efficacy in three murine models, one of which showed more immunogenic characteristics than the others. Results: Myelomodulatory therapy with pexidartinib, a small molecule inhibitor of CSF1R tyrosine kinase, and the oncolytic herpes simplex virus T-VEC exhibited the most significant increase in median survival time in the highly immunogenic model. Additionally, targeting myeloid cells with the myelomodulatory therapy trabectedin, a small molecule activator of caspase-8 dependent apoptosis, augmented the survival benefit of T-VEC in a less immunogenic MPNST model. However, tumor regressions or shrinkages were not observed. Depletion experiments confirmed that the enhanced survival benefit relied on a T cell response. Furthermore, flow cytometry analysis following combination viroimmunotherapy revealed decreased M2 macrophages and myeloid-derived suppressor cells and increased tumor-specific gp70+ CD8 T cells within the tumor microenvironment. Discussion: In summary, our findings provide compelling evidence for the potential to leverage viroimmunotherapy with myeloid cell targeting against MPNST and warrant further investigation.
Assuntos
Modelos Animais de Doenças , Terapia Viral Oncolítica , Microambiente Tumoral , Animais , Terapia Viral Oncolítica/métodos , Camundongos , Microambiente Tumoral/imunologia , Vírus Oncolíticos/imunologia , Vírus Oncolíticos/genética , Linhagem Celular Tumoral , Imunoterapia/métodos , Humanos , Terapia Combinada , Feminino , Camundongos Endogâmicos C57BL , Neoplasias de Bainha Neural/terapia , Neoplasias de Bainha Neural/imunologia , Neoplasias de Bainha Neural/genética , Aminopiridinas , PirróisRESUMO
Recent studies have indicated that combining oncolytic viruses with CAR-T cells in therapy has shown superior anti-tumor effects, representing a promising approach. Nonetheless, the localized delivery method of intratumoral injection poses challenges for treating metastatic tumors or distal tumors that are difficult to reach. To address this obstacle, we employed HSV-1-infected CAR-T cells, which systemically delivery HSV into solid tumors. The biological function of CAR-T cells remained intact after loading them with HSV for a period of three days. In both immunocompromised and immunocompetent GBM orthotopic mouse models, B7-H3 CAR-T cells effectively delivered HSV to tumor lesions, resulting in enhanced T-cell infiltration and significantly prolonged survival in mice. We also employed a bilateral subcutaneous tumor model and observed that the group receiving intratumoral virus injection exhibited a significant reduction in tumor volume on the injected side, while the group receiving intravenous infusion of CAR-T cells carrying HSV displayed suppressed tumor growth on both sides. Hence, CAR-THSV cells offer notable advantages in the systemic delivery of HSV to distant tumors. In conclusion, our findings emphasize the potential of CAR-T cells as carriers for HSV, presenting significant advantages for oncolytic virotherapy targeting distant tumors.
Assuntos
Imunoterapia Adotiva , Terapia Viral Oncolítica , Vírus Oncolíticos , Receptores de Antígenos Quiméricos , Animais , Camundongos , Terapia Viral Oncolítica/métodos , Humanos , Vírus Oncolíticos/imunologia , Vírus Oncolíticos/genética , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Herpesvirus Humano 1/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Linfócitos T/imunologia , Feminino , Glioblastoma/terapia , Glioblastoma/imunologiaRESUMO
Hepatocellular carcinoma is a refractory tumor with poor prognosis and high mortality. Many oncolytic viruses are currently being investigated for the treatment of hepatocellular carcinoma. Based on previous studies, we constructed a recombinant GM-CSF-carrying Sindbis virus, named SINV-GM-CSF, which contains a mutation (G to S) at amino acid 285 in the nsp1 protein of the viral vector. The potential of this mutated vector for liver cancer therapy was verified at the cellular level and in vivo, respectively, and the changes in the tumor microenvironment after treatment were also described. The results showed that the Sindbis virus could effectively infect hepatocellular carcinoma cell lines and induce cell death. Furthermore, the addition of GM-CSF enhanced the tumor-killing effect of the Sindbis virus and increased the number of immune cells in the intra-tumor microenvironment during the treatment. In particular, SINV-GM-CSF was able to efficiently kill tumors in a mouse tumor model of hepatocellular carcinoma by regulating the elevation of M1-type macrophages (which have a tumor-resistant ability) and the decrease in M2-type macrophages (which have a tumor-promoting capacity). Overall, SINV-GM-CSF is an attractive vector platform with clinical potential for use as a safe and effective oncolytic virus.
Assuntos
Carcinoma Hepatocelular , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Neoplasias Hepáticas , Terapia Viral Oncolítica , Vírus Oncolíticos , Sindbis virus , Microambiente Tumoral , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Carcinoma Hepatocelular/terapia , Animais , Sindbis virus/genética , Sindbis virus/fisiologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas/genética , Camundongos , Terapia Viral Oncolítica/métodos , Humanos , Vírus Oncolíticos/genética , Vírus Oncolíticos/fisiologia , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Macrófagos/metabolismo , Macrófagos/imunologiaRESUMO
In general, ensuring safety is the top priority of a new modality. Although oncolytic virus armed with an immune stimulatory transgene (OVI) showed some promise, the strategic concept of simultaneously achieving maximum effectiveness and minimizing side effects has not been fully explored. We generated a variety of survivin-responsive "conditionally replicating adenoviruses that can target and treat cancer cells with multiple factors (m-CRAs)" (Surv.m-CRAs) armed with the granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene downstream of various promoters using our m-CRA platform technology. We carefully analyzed both therapeutic and adverse effects of them in the in vivo syngeneic Syrian hamster cancer models. Surprisingly, an intratumor injection of a conventional OVI, which expresses the GM-CSF gene under the constitutively and strongly active "cytomegalovirus enhancer and ß-actin promoter", provoked systemic and lethal GM-CSF circulation and shortened overall survival (OS). In contrast, a new conceptual type of OVI, which expressed GM-CSF under the cancer-predominant and mildly active E2F promoter or the moderately active "Rous sarcoma virus long terminal repeat", not only abolished lethal adverse events but also prolonged OS and systemic anti-cancer immunity. Our study revealed a novel concept that optimal expression levels of an immune stimulatory transgene regulated by a suitable upstream promoter is crucial for achieving high safety and maximal therapeutic effects simultaneously in OVI therapy. These results pave the way for successful development of the next-generation OVI and alert researchers about possible problems with ongoing clinical trials.