Oncolytic measles vaccines encoding PD-1 and PD-L1 checkpoint blocking antibodies to increase tumor-specific T cell memory

Veinalde, Rūta; Pidelaserra-Martí, Gemma; Moulin, Coline; Jeworowski, Lara M.; Küther, Linda; Buchholz, Christian J.; Jäger, Dirk; Ungerechts, Guy; Engeland, Christine E.

doi:10.1016/j.omto.2021.11.020

Cited by 14 publications

(13 citation statements)

References 59 publications

(83 reference statements)

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“…Of note, expression of programmed death ligand-1 (PDL-1) was found in CDV-infected lungs by transcriptome analysis (cluster 1) in the present study, which acts as negative regulator of T cell effector responses and IL-2 transcription [ 116 , 117 ]. Interestingly, blockage of the programmed cell death-1/PDL-1 checkpoint pathway by measles virus enhances effector memory T cell response in vitro and in mouse models, representing a potential target for immunotherapy [ 118 , 119 , 120 ]. Noteworthy, immunomodulatory cytokines such as IL-4, IL-10 and TGF-β showed no significant changes in CDV-infected lung tissue in the present study.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and Transcriptional Changes of Pulmonary Immune Responses in Dogs Following Canine Distemper Virus Infection

Chludzinski¹,

Klemens²,

Ciurkiewicz³

et al. 2022

IJMS

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Canine distemper virus (CDV), a morbillivirus within the family Paramyxoviridae, is a highly contagious infectious agent causing a multisystemic, devastating disease in a broad range of host species, characterized by severe immunosuppression, encephalitis and pneumonia. The present study aimed at investigating pulmonary immune responses of CDV-infected dogs in situ using immunohistochemistry and whole transcriptome analyses by bulk RNA sequencing. Spatiotemporal analysis of phenotypic changes revealed pulmonary immune responses primarily driven by MHC-II+, Iba-1+ and CD204+ innate immune cells during acute and subacute infection phases, which paralleled pathologic lesion development and coincided with high viral loads in CDV-infected lungs. CD20+ B cell numbers initially declined, followed by lymphoid repopulation in the advanced disease phase. Transcriptome analysis demonstrated an increased expression of transcripts related to innate immunity, antiviral defense mechanisms, type I interferon responses and regulation of cell death in the lung of CDV-infected dogs. Molecular analyses also revealed disturbed cytokine responses with a pro-inflammatory M1 macrophage polarization and impaired mucociliary defense in CDV-infected lungs. The exploratory study provides detailed data on CDV-related pulmonary immune responses, expanding the list of immunologic parameters potentially leading to viral elimination and virus-induced pulmonary immunopathology in canine distemper.

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Section: Discussionmentioning

confidence: 99%

Phenotypic and Transcriptional Changes of Pulmonary Immune Responses in Dogs Following Canine Distemper Virus Infection

Chludzinski¹,

Klemens²,

Ciurkiewicz³

et al. 2022

IJMS

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“…We and others have previously reported efficacy of MV and ICB combination therapy in immunocompetent mouse models of melanoma, colorectal cancer, and glioblastoma ( 6 – 10 ). These studies showed delayed tumor progression and prolonged survival, an increased intratumoral T cell infiltration, an increased ratio of effector to regulatory T cells, and enhancement of tumor-specific T cell responses upon MV and ICB combination treatment.…”

Section: Introductionmentioning

confidence: 88%

Virotherapy combined with anti-PD-1 transiently reshapes the tumor immune environment and induces anti-tumor immunity in a preclinical PDAC model

et al. 2023

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IntroductionPancreatic ductal adenocarcinoma (PDAC) is largely refractory to cancer immunotherapy with PD-1 immune checkpoint blockade (ICB). Oncolytic virotherapy has been shown to synergize with ICB. In this work, we investigated the combination of anti-PD-1 and oncolytic measles vaccine in an immunocompetent transplantable PDAC mouse model.MethodsWe characterized tumor-infiltrating T cells by immunohistochemistry, flow cytometry and T cell receptor sequencing. Further, we performed gene expression profiling of tumor samples at baseline, after treatment, and when tumors progressed. Moreover, we analyzed systemic anti-tumor and anti-viral immunity.ResultsCombination treatment significantly prolonged survival compared to monotherapies. Tumor-infiltrating immune cells were increased after virotherapy. Gene expression profiling revealed a unique, but transient signature of immune activation after combination treatment. However, systemic anti-tumor immunity was induced by virotherapy and remained detectable even when tumors progressed. Anti-PD-1 treatment did not impact anti-viral immunity.DiscussionOur results indicate that combined virotherapy and ICB induces anti-tumor immunity and reshapes the tumor immune environment. However, further refinement of this approach may be required to develop its full potential and achieve durable efficacy.

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“…[151] Recently, an interesting study revealed that combination therapy using oncolytic measles vaccine (MV) vectors encoding anti-PD-1 or anti-PD-L1 genes and PD-1/PD-L1 blockers leads to a slight increase in survival and intratumoral IFN-γ compared with monotherapy by control MV or anti-PD-1/PD-L1 antibodies. [152] Therefore, combining oncolytic viruses encoding cytokine genes (TNF-α, IL-2, IL-12, IFN-γ) with anti-PD-1/PD-L1 antibodies can be more effective in the treatment than anti-PD-1 or anti-PD-L1 encoding MVs and anti-PD-1/PD-L1 antibodies. A thymidine kinase (TK) gene deleted oncolytic vaccinia virus (ΔTK-Armed-VACV) encoding anti-PD-1, and anti-4-1BB (CD137) antibody genes were designed to treat cancer.…”

Section: Anti Pd-1 and Anti Pd-l1 Antibodiesmentioning

confidence: 99%

Combining of Oncolytic Virotherapy and Other Immunotherapeutic Approaches in Cancer: A Powerful Functionalization Tactic

2022

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to direct lysis of these cells. [4] In addition, oncolytic viruses can stimulate immune responses. The most studied oncolytic viruses are Newcastle disease viruses, herpes viruses, coxsackievirus, measles viruses, adenoviruses, polioviruses, poxviruses, and reoviruses. [5,6] Therefore, oncolytic viruses can be a moral treatment option in cancer therapy. The unique feature of oncolytic viruses is that they act selectively and remove tumor cells without damaging non-cancerous cells. [7] Initially, oncolytic virotherapy was studied as monotherapy with unsatisfactory therapeutic effectiveness. Several mechanisms, including the immunosuppressive tumor microenvironment (TME), the off-target sequestration and replication, the existence of neutralizing antibodies, and the balance between viral replication and induced immune response, contribute to oncolytic virotherapy monotherapy resistance. [8] Therefore, researchers have used various combination therapies to overcome these barriers using oncolytic viruses and immunotherapy.Cancer immunotherapy, including methods such as adoptive T cell therapy, immune checkpoint blockade, and monoclonal or bispecific antibodies, has recently succeeded in treating cancer and other immune-related diseases such as autoimmunity. [9][10][11] Oncolytic viruses have found a good place in the treatment of cancer. Administering oncolytic viruses directly or by applying genetic changes can be effective in cancer treatment through the lysis of tumor cells and, in some cases, by inducing immune system responses. Moreover, oncolytic viruses induce antitumor immune responses via releasing tumor antigens in the tumor microenvironment (TME) and affect tumor cell growth and metabolism. Despite the success of virotherapy in cancer therapies, there are several challenges and limitations, such as immunosuppressive TME, lack of effective penetration into tumor tissue, low efficiency in hypoxia, antiviral immune responses, and off-targeting. Evidence suggests that oncolytic viruses combined with cancer immunotherapy-based methods such as immune checkpoint inhibitors and adoptive cell therapies can effectively overcome these challenges. This review summarizes the latest data on the use of oncolytic viruses for the treatment of cancer and the challenges of this method. Additionally, the effectiveness of mono, dual, and triple therapies using oncolytic viruses and other anticancer agents has been discussed based on the latest findings.

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Oncolytic measles vaccines encoding PD-1 and PD-L1 checkpoint blocking antibodies to increase tumor-specific T cell memory

Cited by 14 publications

References 59 publications

Phenotypic and Transcriptional Changes of Pulmonary Immune Responses in Dogs Following Canine Distemper Virus Infection

Phenotypic and Transcriptional Changes of Pulmonary Immune Responses in Dogs Following Canine Distemper Virus Infection

Virotherapy combined with anti-PD-1 transiently reshapes the tumor immune environment and induces anti-tumor immunity in a preclinical PDAC model

Combining of Oncolytic Virotherapy and Other Immunotherapeutic Approaches in Cancer: A Powerful Functionalization Tactic

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