Concepts in Oncolytic Adenovirus Therapy

Mantwill, Klaus; Klein, Florian G; Wang, Dongbiao; Hindupur, Sruthi Vasantamadhava; Ehrenfeld, Maximilian; Holm, Per Sonne; Nawroth, Roman

doi:10.3390/ijms221910522

Cited by 60 publications

(47 citation statements)

References 114 publications

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“…In contrast, cell viability experiments carried out on B16V and AB12 demonstrated that tested virus was able to infect and induce cell death in those cell lines, especially at a concentration of 100 VP/cell (cell viability was 40.4% and 44.7% for B16V and AB12, respectively) (Figure S1). This is not surprising as it is known that genetically modified adenovirus, delta-24, which has a 24-base pair deletion in the Rb-binding region of the E1A gene, shows selective replication and oncolysis in various malignant cells [37,38]. Expression level of adenovirus cell entry receptors on the surface of cancer cells show that the B16V and AB12 cell line expressed DSG2 receptors (approximately 21% and 98% of cells positive for the marker respectively).…”

Section: Resultsmentioning

confidence: 93%

From Immunosuppression to Immunomodulation - Turning Cold Tumours into Hot

Garofalo¹,

Pancer²,

Wieczorek³

et al. 2022

J. Cancer

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Cancer cells employ various mechanisms to evade and suppress anti-cancer immune responses generating a "cold" immunosuppressive tumour microenvironment. Oncolytic viruses are a promising tool to convert tumour immunosuppression to immunomodulation and improve the efficacy of cancer treatment. Emerging preclinical and clinical findings confirm that oncolytic viruses act in a multimodal scheme, triggering lyses, immunogenic cell death and finally inducing anti-cancer immune responses. In this paper, we tested the local administration of a novel oncolytic adenovirus AdV-D24-ICOSL-CD40L expressing co-stimulatory molecules ICOSL and CD40L to induce the production of tumour infiltrating lymphocytes to the site of injection. Subsequently, in immunocompetent mouse models, we studied possible correlation between tumour infiltrates and anti-cancer efficacy. Described results showed that the delivery of oncolytic viruses encoding immunomodulatory transgenes in combination with anti-PD1 resulted in synergistic inhibition of both melanoma and mesothelioma tumours. Importantly anti-cancer effect positively correlated with cytotoxic CD8+ tumour-infiltrating lymphocytes exerting a central role in the tumour volume control thus generating beneficial outcomes that will undoubtedly provide new insights into possible future treatment strategies to combat cancer. Altogether our findings highlight the importance of oncolytic vectors able to modulate anti-cancer immune responses that can correlate with efficacy in solid malignancies.

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Section: Resultsmentioning

confidence: 93%

From Immunosuppression to Immunomodulation - Turning Cold Tumours into Hot

Garofalo¹,

Pancer²,

Wieczorek³

et al. 2022

J. Cancer

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“…The xenograft models used in this manuscript also prove that in a 3-dimensional in vivo situation, the combination therapy used results in a much better oncolytic potency which corresponds to better replication compared to the virus monotherapy. However, for clinical purposes a humanized patient-derived xenograft model would be beneficial since the therapeutic effect of oncolytic viruses strongly depends on activating an anti-cancer immune response in vivo 56 .…”

Section: Discussionmentioning

confidence: 99%

Targeting the Retinoblastoma/E2F repressive complex by CDK4/6 inhibitors amplifies oncolytic potency of an oncolytic adenovirus

et al. 2022

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CDK4/6 inhibitors (CDK4/6i) and oncolytic viruses are promising therapeutic agents for the treatment of various cancers. As single agents, CDK4/6 inhibitors that are approved for the treatment of breast cancer in combination with endocrine therapy cause G1 cell cycle arrest, whereas adenoviruses induce progression into S-phase in infected cells as an integral part of the their life cycle. Both CDK4/6 inhibitors and adenovirus replication target the Retinoblastoma protein albeit for different purposes. Here we show that in combination CDK4/6 inhibitors potentiate the anti-tumor effect of the oncolytic adenovirus XVir-N-31 in bladder cancer and murine Ewing sarcoma xenograft models. This increase in oncolytic potency correlates with an increase in virus-producing cancer cells, enhanced viral genome replication, particle formation and consequently cancer cell killing. The molecular mechanism that regulates this response is fundamentally based on the reduction of Retinoblastoma protein expression levels by CDK4/6 inhibitors.

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“…In the present study, a maximum of three doses of ICOCAV15 were administered (one dog with one dose, five dogs with two doses, and two dogs with three doses). We believed it would be more effective, given that 90% of the virus had been eliminated intravenously within the first 24 h by elements of the immune system, and even if cell-mediated delivery is a way to avoid such elimination, there is still a risk of it occurring [ 45 , 46 ]. The patients included in the study were only those that had accessible tumors, to avoid administration-associated risks.…”

Section: Discussionmentioning

confidence: 99%

Safety and Efficacy of an Oncolytic Adenovirus as an Immunotherapy for Canine Cancer Patients

Martín-Carrasco

Delgado-Bonet

Tomeo-Martín

et al. 2022

Veterinary Sciences

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The use of oncolytic viruses is an innovative approach to lyse tumor cells and induce antitumor immune responses. Eight dogs diagnosed with carcinoma/adenocarcinoma were intratumorally treated with ICOCAV15, an oncolytic canine adenovirus (CAV). To evaluate the treatment’s safety, a blood count, biochemistry, and coagulation test were performed before treatment and during follow-up. Immune populations were analyzed by flow cytometry. Anti-adenovirus antibodies were also determined. The immune infiltration, vascularization, and viral presence in the tumor were determined by CD3, CD4, CD20, CD31 and CAV by immunohistochemistry. All the dogs maintained a good quality of life during follow-up, and some had increased median survival time when compared with dogs treated with chemotherapy. No treatment-related adverse effects were detected. The Response Evaluation Criteria In Solid Tumors criteria were also assessed: two patients showed a partial response and the rest showed stable disease at various times during the study. ICOCAV15 was detected inside the tumor during follow-up, and antiviral antibodies were detected in all patients. Furthermore, the tumor-infiltrating immune cells increased after viral administration. Therefore, we suggest that intratumorally administered ICOCAV15 could represent as a new tool for the treatment of canine carcinoma because it is safe, well-tolerated by dogs, and shows promising results.

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Concepts in Oncolytic Adenovirus Therapy

Cited by 60 publications

References 114 publications

From Immunosuppression to Immunomodulation - Turning Cold Tumours into Hot

From Immunosuppression to Immunomodulation - Turning Cold Tumours into Hot

Targeting the Retinoblastoma/E2F repressive complex by CDK4/6 inhibitors amplifies oncolytic potency of an oncolytic adenovirus

Safety and Efficacy of an Oncolytic Adenovirus as an Immunotherapy for Canine Cancer Patients

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