Immunotherapeutic Potential of TGF-β Inhibition and Oncolytic Viruses

Groeneveldt, Christianne; Hall, Thorbald van; Burg, Sjoerd H. van der; Dijke, Peter ten; Montfoort, Nadine van

doi:10.1016/j.it.2020.03.003

Cited by 57 publications

(49 citation statements)

References 116 publications

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“…Reovirus and other OVs have already demonstrated to combine well with checkpoint blockade, a therapy that depends on the presence of tumor-specific T cells. [10][11][12] OVs and T-cell-engaging antibody therapy is an emerging and exciting new field of research. We demonstrated that prior sensitization with reovirus greatly enhanced the efficacy of CD3-bsAb therapy in immunologically cold tumors.…”

Section: Discussionmentioning

confidence: 99%

Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy

Groeneveldt

Kinderman

Wollenberg

et al. 2020

J Immunother Cancer

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BackgroundT-cell-engaging CD3-bispecific antibodies (CD3-bsAbs) are promising modalities for cancer immunotherapy. Although this therapy has reached clinical practice for hematological malignancies, the absence of sufficient infiltrating T cells is a major barrier for efficacy in solid tumors. In this study, we exploited oncolytic reovirus as a strategy to enhance the efficacy of CD3-bsAbs in immune-silent solid tumors.MethodsThe mutant p53 and K-ras induced murine pancreatic cancer model KPC3 resembles human pancreatic ductal adenocarcinomas with a desmoplastic tumor microenvironment, low T-cell density and resistance to immunotherapy. Immune-competent KPC3 tumor-bearing mice were intratumorally injected with reovirus type 3 Dearing strain and the reovirus-induced changes in the tumor microenvironment and spleen were analyzed over time by NanoString analysis, quantitative RT-PCR and multicolor flow cytometry. The efficacy of reovirus in combination with systemically injected CD3-bsAbs was evaluated in immune-competent mice with established KPC3 or B16.F10 tumors, and in the close-to-patient human epidermal growth factor receptor 2 (HER2)+ breast cancer model BT474 engrafted in immunocompromised mice with human T cells as effector cells.ResultsReplication-competent reovirus induced an early interferon signature, followed by a strong influx of natural killer cells and CD8+ T cells, at the cost of FoxP3+ Tregs. Viral replication declined after 7 days and was associated with a systemic activation of lymphocytes and the emergence of intratumoral reovirus-specific CD8+ T cells. Although tumor-infiltrating T cells were mostly reovirus-specific and not tumor-specific, they served as non-exhausted effector cells for the subsequently systemically administered CD3-bsAbs. Combination treatment of reovirus and CD3-bsAbs led to the regression of large, established KPC3, B16.F10 and BT474 tumors. Reovirus as a preconditioning regimen performed significantly better than simultaneous or early administration of CD3-bsAbs. This combination treatment induced regressions of distant lesions that were not injected with reovirus, and systemic administration of both reovirus and CD3-bsAbs also led to tumor control. This suggests that this therapy might also be effective for metastatic disease.ConclusionsOncolytic reovirus administration represents an effective strategy to induce a local interferon response and strong T-cell influx, thereby sensitizing the tumor microenvironment for subsequent CD3-bsAb therapy. This combination therapy warrants further investigation in patients with non-inflamed solid tumors.

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Section: Discussionmentioning

confidence: 99%

Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy

Groeneveldt

Kinderman

Wollenberg

et al. 2020

J Immunother Cancer

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“…While the use of immune checkpoint inhibitors alone may favor the cytolytic activity of immune cells that are present within the cancer mass, their combination with TGF-β pharmacological inhibitors may increase the infiltration of these cells in "cold tumors." More details about the synergism between TGF-β pharmacological inhibitors and immune checkpoint inhibitors has been reviewed and discussed by others regarding its use in pre-clinical models and clinical trials (Ganesh and Massagué, 2018;Bai et al, 2019;Groeneveldt et al, 2020;Lind et al, 2020).…”

Section: Other Perspectivesmentioning

confidence: 99%

On-Target Anti-TGF-β Therapies Are Not Succeeding in Clinical Cancer Treatments: What Are Remaining Challenges?

Teixeira

Dijke

Zhu

2020

Front. Cell Dev. Biol.

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Metastasis is the leading cause of death for cancer patients. During cancer progression, the initial detachment of cells from the primary tumor and the later colonization of a secondary organ are characterized as limiting steps for metastasis. Epithelialmesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are opposite dynamic multistep processes that enable these critical events in metastasis by altering the phenotype of cancer cells and improving their ability to migrate, invade and seed at distant organs. Among the molecular pathways that promote tumorigenesis in late-stage cancers, transforming growth factor-β (TGF-β) is described as an EMT master inducer by controlling different genes and proteins related to cytoskeleton assembly, cell-cell attachment and extracellular matrix remodeling. Still, despite the successful outcomes of different TGF-β pharmacological inhibitors in cell culture (in vitro) and animal models (in vivo), results in cancer clinical trials are poor or inconsistent at least, highlighting the existence of crucial components in human cancers that have not been properly explored. Here we review most recent findings to provide perspectives bridging the gap between on-target anti-TGF-β therapies in vitro and in pre-clinical models and the poor clinical outcomes in treating cancer patients. Specifically, we focus on (i) the dual roles of TGF-β signaling in cancer metastasis; (ii) dynamic signaling; (iii) functional differences of TGF-β free in solution vs. in exosomes; (iv) the regulatory effects of tumor microenvironment (TME)-particularly by cancer-associated fibroblasts-on TGF-β signaling pathway. Clearly identifying and establishing those missing links may provide strategies to revitalize and clinically improve the efficacy of TGF-β targeted therapies.

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“…Greater knowledge of the function of viral genes and advancements in molecular biology have significantly improved the safety and efficacy of OVs. The basis of the therapeutic efficacy of OVs is considered to be the recruitment of T cells and induction of tumor-reactive immunity ( 42 ). Studies have indicated that delivering OVs into the tumor can facilitate a strong and durable response against the tumor by stimulating the activity of the immune system ( 43 , 44 ).…”

Section: Immunotherapymentioning

confidence: 99%

“…Talimogene laherparepvec is the only approved OV in the US to date ( 45 ). In addition, the use of an OV in combination with inhibition of transforming growth factor-β signaling is thought to increase the efficacy of immunotherapy ( 42 ). According to a recent study, a novel Vaccinia virus known as VVΔTKΔN1L , with thymidine kinase and N1L gene deletions and armed with interleukin 12, successfully prevented the recurrence of tumors in surgical models of head and neck cancer in Syrian hamsters ( 46 ).…”

Section: Immunotherapymentioning

confidence: 99%

Latest evidence on immunotherapy for cholangiocarcinoma (Review)

Guo

Shen

2020

Oncol Lett

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Cholangiocarcinoma (CCA) is a type of aggressive tumor that involves the intrahepatic, perihilar and distal biliary tree, and is usually diagnosed at an advanced stage. The standard first-line systemic therapy for patients with advanced CCA is a combination of gemcitabine and cisplatin; targeted therapies and angiogenesis inhibitors are not widely used clinically at present. However, with the development of precision medicine, immunotherapy has started to play a more important role. Programmed cell death protein 1 inhibitors are now considered a good therapeutic option for CCA. Treatments using chimeric antigen receptor T cells, bispecific antibodies, oncolytic viruses and cancer vaccines have also achieved satisfactory results. In addition, combinations of immunotherapy with a variety of conventional therapies have shown some efficacy, and several studies have provided insights into their use in antitumor therapy. Although there are numerous challenges in the treatment of advanced CCA, immunotherapy remains a noteworthy breakthrough. The current evidence on the immunotherapy of CCA is discussed in the present review.

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Immunotherapeutic Potential of TGF-β Inhibition and Oncolytic Viruses

Cited by 57 publications

References 116 publications

Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy

Preconditioning of the tumor microenvironment with oncolytic reovirus converts CD3-bispecific antibody treatment into effective immunotherapy

On-Target Anti-TGF-β Therapies Are Not Succeeding in Clinical Cancer Treatments: What Are Remaining Challenges?

Latest evidence on immunotherapy for cholangiocarcinoma (Review)

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