Mesenchymal stem cells as carriers for systemic delivery of oncolytic viruses

Hadryś, Agata; Sochanik, Aleksander; McFadden, Grant; Jazowiecka-Rakus, Joanna

doi:10.1016/j.ejphar.2020.172991

Cited by 54 publications

(38 citation statements)

References 145 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 47 Stand-alone oncolytic virotherapies are unlikely to yield complete tumor regression, except in “elite responders.” 48 Thus, MSCs engineered to enhance tumor tropism, novel MYXV constructs with antiapoptotic genes, 25 suicide genes, 49 anti-angiogenesis factors, 50 host response immunomodulatory cytokines, 51 , 52 and combinations with nanotherapeutics 32 , 53 , 54 are likely to be developed. 55 We show here that infected human MSCs can transfer progeny MYXV to melanoma cells and that accumulation of IL-15-expressing MYXV in murine lung lesions following delivery by MSCs can reduce tumor burden and trigger inflow of CD8+ cells.…”

Section: Discussionmentioning

confidence: 71%

Myxoma Virus-Loaded Mesenchymal Stem Cells in Experimental Oncolytic Therapy of Murine Pulmonary Melanoma

Jazowiecka-Rakus

Sochanik

Rusin

et al. 2020

Molecular Therapy - Oncolytics

Self Cite

View full text Add to dashboard Cite

Oncolytic viruses can target neoplasms, triggering oncolytic and immune effects. Their delivery to melanoma lesions remains challenging. Bone-marrow-derived mesenchymal stem cells (MSCs) were shown to be permissive for oncolytic myxoma virus (MYXV), allowing its transfer to melanoma cells, leading to their killing. Involvement of progeny virus was demonstrated in the transfer from MSCs to co-cultured melanoma cells. The inhibitory effect of virus on melanoma foci formation in murine lungs was revealed using melanoma cells previously co-cultured with MYXV-infected MSCs. Virus accumulation and persistence in lungs of lesion-bearing mice were shown following intravenous administration of MSC-shielded MYXV construct encoding luciferase. Therapy of experimentally induced lung melanoma in mice with interleukin (IL)-15-carrying MYXV construct delivered by MSCs led to marked regression of lesions and could increase survival. Elevated natural killer (NK) cell percentages in blood indicated robust innate responses against unshielded virus only. Lung infiltration by NK cells was followed by inflow of CD8+ T lymphocytes into melanoma lesions. Elevated expression of genes involved in adaptive immune response following oncolytic treatment was confirmed using RT-qPCR. No adverse pathological effects related to MSC-mediated oncolytic therapy with MYXV were observed. MSCs allow for safe and efficient ferrying of therapeutic MYXV to pulmonary melanoma foci triggering immune effects.

show abstract

Section: Discussionmentioning

confidence: 71%

Myxoma Virus-Loaded Mesenchymal Stem Cells in Experimental Oncolytic Therapy of Murine Pulmonary Melanoma

Jazowiecka-Rakus

Sochanik

Rusin

et al. 2020

Molecular Therapy - Oncolytics

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, their delivery to tumor sites is still challenging, and only a limited fraction of oncolytic viruses manages to reach the target tumor after systemic administration of the therapy, as they are cleared by the immune system [ 3 ]. The use of mesenchymal stem cells (MSCs) as cell vehicles for virus delivery applications has been considered, then, as an alternative to intravenous or intratumoral administration of the oncolytic virus alone, as MSCs present tropism for tumors [ 4 , 5 ]. In this way, this cellular virotherapy can be administered in cases in which the tumor is not accessible and may even act in tumors or metastases that have not been found.…”

Section: Introductionmentioning

confidence: 99%

“…These and other studies have demonstrated that adaptive immune subsets like CD8 + T cells are crucial mediators of the induced antitumor immunity in patients treated with oncolytic virotherapies [ 17 , 18 ]. Nevertheless, although some immunocompetent mouse models have been developed [ 5 , 19 , 20 ], most commonly used preclinical models for studying oncolytic viruses are immunodeficient, which might not represent the real mechanism of action of these viroimmunotherapies, as they present later clearance, higher viral replication, and increased antitumor effects compared to immunocompetent hosts [ 21 ]. In addition, most mouse cells are refractory to the replication of human adenovirus, and as a result, the study of human OAd has been almost restricted to xenograft mouse models, which need to be performed in immunodeficient mice.…”

Section: Introductionmentioning

confidence: 99%

Cellular Virotherapy Increases Tumor-Infiltrating Lymphocytes (TIL) and Decreases their PD-1+ Subsets in Mouse Immunocompetent Models

Morales-Molina

Rodríguez-Milla

Gimenez-Sanchez

et al. 2020

Cancers

View full text Add to dashboard Cite

Oncolytic virotherapy uses viruses designed to selectively replicate in cancer cells. An alternative to intratumoral administration is to use mesenchymal stem cells (MSCs) to transport the oncolytic viruses to the tumor site. Following this strategy, our group has already applied this treatment to children and adults in a human clinical trial and a veterinary trial, with good clinical responses and excellent safety profiles. However, the development of immunocompetent cancer mouse models is still necessary for the study and improvement of oncolytic viroimmunotherapies. Here we have studied the antitumor efficacy, immune response, and mechanism of action of a complete murine version of our cellular virotherapy in mouse models of renal adenocarcinoma and melanoma. We used mouse MSCs infected with the mouse oncolytic adenovirus dlE102 (OAd-MSCs). In both models, treatment with OAd-MSCs significantly reduced tumor volumes by 50% and induced a pro-inflammatory tumor microenvironment. Furthermore, treated mice harboring renal adenocarcinoma and melanoma tumors presented increased infiltration of tumor-associated macrophages (TAMs), natural killer cells, and tumor-infiltrating lymphocytes (TILs). Treated mice also presented lower percentage of TILs expressing programmed cell death protein 1 (PD-1)—the major regulator of T cell exhaustion. In conclusion, treatment with OAd-MSCs significantly reduced tumor volume and induced changes in tumor-infiltrating populations of melanoma and renal cancer.

show abstract

“…Although no complete response was reported, anti-tumour response was observed in distant sites from the sites of T-VEC intratumoural injection, highlighting the potential of this combination therapy for metastatic sarcoma [132]. Studies have also investigated loading oncolytic virus into mesenchymal stem cells (MSCs) to enhance delivery of these viruses to tumour sites and to shield these viruses from inducing anti-viral immune response before reaching the tumour bed [133]. The effects of MSCs have on TME and immune cells still remain largely unknown but Mahasa et al utilised a mathematical experimental model approach to examine the immune responses elicited by MSCs loaded with oncolytic viruses [134].…”

Section: Oncolytic Virus Therapymentioning

confidence: 99%

Will Next-Generation Immunotherapy Overcome the Intrinsic Diversity and Low Immunogenicity of Sarcomas to Improve Clinical Benefit?

Chew

Chan

Simpson

et al. 2020

Cancers

View full text Add to dashboard Cite

Sarcomas are a rare type of a heterogeneous group of tumours arising from mesenchymal cells that form connective tissues. Surgery is the most common treatment for these tumours, but additional neoadjuvant or adjuvant chemotherapy or radiation therapies may be necessary. Unfortunately, a significant proportion of patients treated with conventional therapies will develop metastatic disease that is resistant to therapies. Currently, there is an urgent need to develop more effective and durable therapies for the treatment of sarcomas. In recent years immunotherapies have revolutionised the treatment of a variety of cancers by restoring patient anti-tumour immune responses or through the adoptive infusion of immune effectors able to kill and eliminate malignant cells. The clinicopathologic and genetic heterogeneity of sarcomas, together with the generally low burden of somatic mutations potentially generating neoantigens, are currently limited to broad application of immunotherapy for patients with sarcomas. Nevertheless, a better understanding of the microenvironmental factors hampering the efficacy of immunotherapy and the identification of new and suitable therapeutic targets may help to overcome current limitations. Moreover, the recent advances in the development of immunotherapies based on the direct exploitation or targeting of T cells and/or NK cells may offer new opportunities to improve the treatment of sarcomas, particularly those showing recurrence or resistance to standard of care treatments.

show abstract

Mesenchymal stem cells as carriers for systemic delivery of oncolytic viruses

Cited by 54 publications

References 145 publications

Myxoma Virus-Loaded Mesenchymal Stem Cells in Experimental Oncolytic Therapy of Murine Pulmonary Melanoma

Myxoma Virus-Loaded Mesenchymal Stem Cells in Experimental Oncolytic Therapy of Murine Pulmonary Melanoma

Cellular Virotherapy Increases Tumor-Infiltrating Lymphocytes (TIL) and Decreases their PD-1+ Subsets in Mouse Immunocompetent Models

Will Next-Generation Immunotherapy Overcome the Intrinsic Diversity and Low Immunogenicity of Sarcomas to Improve Clinical Benefit?

Contact Info

Product

Resources

About