Harnessing combined p19Arf and interferon-beta gene transfer as an inducer of immunogenic cell death and mediator of cancer immunotherapy

Hunger, Aline; Medrano, Ruan F.V.; Strauss, Bryan E.

doi:10.1038/cddis.2017.201

Cited by 10 publications

(13 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Microarray analysis of B16 cells after ex vivo gene transfer revealed increased expression of genes associated with the immune response, p53 activity, cell death and antiviral response and decreased expression of cell cycle-related transcripts. Therefore, the multimodal cell death mechanism was consistent with necroptosis associated with the release of ICD markers and an antiviral response 31 , 32 .…”

Section: Introductionmentioning

confidence: 59%

“…In a later study, we examined both the critical aspects of the adenovirus-mediated gene transfer and the specific mechanism of cell death in response to p19Arf and IFNβ gene transfer. In this work, improvements to vector design involved the use of the RGD tripeptide included in the knob domain of the adenovirus fiber protein, thus broadening the spectrum of cells that may be transduced since virus-cell interaction depends on integrins but not the coxsackievirus and adenovirus receptor 30-32 . We also explored the use of a single vector for the simultaneous transfer of the p19Arf and IFNβ cDNA, finding that both co-transduction and IRES-mediated expression of two proteins from a single transcript were equally effective 32 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Perspectives for cancer immunotherapy mediated by p19Arf plus interferon-beta gene transfer

Strauss¹,

Silva²,

Vieira³

et al. 2018

Clinics

Self Cite

View full text Add to dashboard Cite

While cancer immunotherapy has gained much deserved attention in recent years, many areas regarding the optimization of such modalities remain unexplored, including the development of novel approaches and the strategic combination of therapies that target multiple aspects of the cancer-immunity cycle. Our own work involves the use of gene transfer technology to promote cell death and immune stimulation. Such immunogenic cell death, mediated by the combined transfer of the alternate reading frame (p14ARF in humans and p19Arf in mice) and the interferon-β cDNA in our case, was shown to promote an antitumor immune response in mouse models of melanoma and lung carcinoma. With these encouraging results, we are now setting out on the road toward translational and preclinical development of our novel immunotherapeutic approach. Here, we outline the perspectives and challenges that we face, including the use of human tumor and immune cells to verify the response seen in mouse models and the incorporation of clinically relevant models, such as patient-derived xenografts and spontaneous tumors in animals. In addition, we seek to combine our immunotherapeutic approach with other treatments, such as chemotherapy or checkpoint blockade, with the goal of reducing dosage and increasing efficacy. The success of any translational research requires the cooperation of a multidisciplinary team of professionals involved in laboratory and clinical research, a relationship that is fostered at the Cancer Institute of Sao Paulo.

show abstract

Section: Introductionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Perspectives for cancer immunotherapy mediated by p19Arf plus interferon-beta gene transfer

Strauss¹,

Silva²,

Vieira³

et al. 2018

Clinics

Self Cite

View full text Add to dashboard Cite

show abstract

“…In a mouse model of lung carcinoma, we have shown that in situ gene therapy can bring about an antitumor immune response with critical involvement of neutrophils [113]. Together these studies show that our gene transfer approach is an effective immunotherapy [114,115]. The results to date are promising and research will continue to evolve, with critical development using clinically relevant models, such as testing with patient-derived tumor samples as well as alternative animal models, including canines [116].…”

Section: Turning Gene Therapy Into Immunotherapy: Adenovirus-carryingmentioning

confidence: 73%

Gene-based Interventions for Cancer Immunotherapy

Cerqueira¹,

Silva²,

LunaVieira³

et al. 2019

In Vivo and Ex Vivo Gene Therapy for Inherited and Non-Inherited Disorders

View full text Add to dashboard Cite

Immunotherapy of cancer has deservedly gained much attention in the past few years and is likely to continue to advance and become a fundamental cancer treatment. While vaccines, chimeric antigen receptor (CAR) T cells and checkpoint blockade have received the lion's share of the attention, an important direct role for gene transfer as an immunotherapy is emerging. For example, oncolytic viruses induce immunogenic cell death, thus liberating both antigens and the signals that are necessary for the activation of antigenpresenting cells, ensuring stimulation of an adaptive response. In another example, transfer of prodrug converting enzymes, such as the herpes simplex virus-thymidine kinase (HSV-tk) gene or the cytosine deaminase gene, has been shown to promote an immune response, thus functioning as immunotherapies. Alternatively, our own work involves the use of nonreplicating viral vectors for the simultaneous delivery of gene combinations that promote both cell death and an immune response. In fact, our gene transfer approach has been applied as a vaccine, immunotherapy or in situ gene therapy, resulting in immunogenic cell death and the induction of a protective immune response. Here, we highlight the development of these approaches both in terms of technical advances and clinical experience.

show abstract

“…In addition, the adenoviral vectors used, AdRGD-PG, were modified to contain improvements at both the transductional (RGDmodified fiber protein) and transcriptional levels (p53responsive chimeric promoter, PG) (13). In this way, the vector and transgenes are expected to work together to promote high level expression, cell death, and anti-tumor immune modulation, points that have been substantiated previously (18,19).…”

Section: Introductionmentioning

confidence: 99%

p19Arf sensitizes B16 melanoma cells to interferon-β delivered via mesenchymal stem cells in vitro

DaCosta

Vieira

Hunger

et al. 2020

Braz J Med Biol Res

View full text Add to dashboard Cite

The immune stimulatory and anti-neoplastic functions of type I interferon have long been applied for the treatment of melanoma. However, the systemic application of high levels of this recombinant protein is often met with toxicity. An approach that provides localized, yet transient, production of type I interferon may overcome this limitation. We propose that the use of mesenchymal stem cells (MSCs) as delivery vehicles for the production of interferon-b (IFNb) may be beneficial when applied together with our cancer gene therapy approach. In our previous studies, we have shown that adenovirus-mediated gene therapy with IFNb was especially effective in combination with p19Arf gene transfer, resulting in immunogenic cell death. Here we showed that MSCs derived from mouse adipose tissue were susceptible to transduction with adenovirus, expressed the transgene reliably, and yet were not especially sensitive to IFNb production. MSCs used to produce IFNb inhibited B16 mouse melanoma cells in a co-culture assay. Moreover, the presence of p19Arf in the B16 cells sensitizes them to the IFNb produced by the MSCs. These data represent a critical demonstration of the use of MSCs as carriers of adenovirus encoding IFNb and applied as an anticancer strategy in combination with p19Arf gene therapy.

show abstract

Harnessing combined p19Arf and interferon-beta gene transfer as an inducer of immunogenic cell death and mediator of cancer immunotherapy

Cited by 10 publications

References 13 publications

Perspectives for cancer immunotherapy mediated by p19Arf plus interferon-beta gene transfer

Perspectives for cancer immunotherapy mediated by p19Arf plus interferon-beta gene transfer

Gene-based Interventions for Cancer Immunotherapy

p19Arf sensitizes B16 melanoma cells to interferon-β delivered via mesenchymal stem cells in vitro

Contact Info

Product

Resources

About