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Potentiating immunotherapy with improved oncolytic viruses
Dr. Geertje Van Der Horst PhD. Researcher Leiden University Medical Center Leiden (NL)
Clinical problem Prostate cancer is the most common cancer in males and the third cause of cancer-related death in men in Europe. [1,2] Current treatments of primary prostate cancer with androgen deprivation therapy are initially very effective. However beneficial responses are followed by tumour recurrence at distant sites leading to incurable, metastatic castration-resistant disease.
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Urothelial carcinoma of the bladder is the sixth most common cancer in Europe. [2] Despite the prevalence and high economic costs, bladder cancer is still relatively understudied. [3] For patients with metastatic UCB, systemic cisplatin-based chemotherapy is the standardof-care. [4] This treatment has considerable side-effects and approximately 30% of patients either fail to respond or suffer recurrent disease within five years.
Immunotherapy has emerged as a viable and attractive strategy for the treatment of solid tumours, including those of the human bladder and prostate. Despite the success of immu-notherapeutic approaches in several tumour types, prostate cancer has remained largely unresponsive. Moreover, only about 30% of patients with metastatic bladder cancer will respond to immune checkpoint inhibition and the development of novel therapy for these urological malignancies is, therefore, needed.
Oncolytic virotherapy Currently, several immunotherapy approaches and combinations are under investigation in numerous clinical trials and various clinical scenarios, including immune checkpoint inhibi-tors (ICIs), cell-based therapy and cancer vaccines. [5-9] ICIs encompass antibodies blocking the PD-1/PD-L1 pathway. These compounds have shown impressive and durable responses in several clinical studies. [10-21] Prostate and bladder cancers frequently escape from im-mune surveillance by creating an immune-suppressive tumour microenvironment. As a re-sult, tumours from these patients remained largely unresponsive to treatment. [22-24] Tak-en together, more effective therapies for high-risk, advanced or metastatic patients are warranted.
Oncolytic viro-immunotherapy is a promising cancer treatment in which replication-competent oncolytic viruses are used that specifically infect, replicate in and lyse malignant tumour cells, while minimising harm to normal cells. [25-26] Infection of tumour cells by oncolytic viruses (OVs) is now also recognised for their immunotherapeutic potential by promoting strong antiviral and antitumour immune responses. Genetically engineered or naturally-occurring OVs can be exploited to kickstart the immune system either alone or combined with current immunotherapies for the treatment of bladder and prostate cancer patients. Worldwide, multiple OVs are under investigation and various clinical trials are ongoing with a.o. Adenovirus (AD), Newcastle Disease virus (NDV), Reovirus (RV) and Her-pes simplex virus (HSV). Although OVs were originally designed to function as tumour-lysing therapeutics, they have now been shown to initiate systemic anti-tumour immune responses (immunogenic cell death or ICD).
Upon oncolysis, tumour cells release damage-associated molecular patterns (DAMPs) [27-28] and pathogenassociated molecular patterns (PAMPs).[27-30] DAMPs and PAMPs are recognised by antigen presenting cells and presented to T-cells thereby initiating a system-ic, adaptive immune response. [31]
It is no longer considered critical for viruses to directly infect and kill every tumour cell. [32, 33] Successful virotherapy results in inducing more effective antitumour immune respons-es and/or reduction of immune suppression that shield tumour cells from the immune sys-tem. [25, 34-40] OVs may, therefore, enhance anti-tumour responses in patients that fail to respond to current immune checkpoint blockade.
The outcomes of clinical trials highlight that the efficacy of oncolytic viro-immunotherapy varies between patients, depending on the tumour type and the applied oncolytic virus. [7,8] The observed heterogeneous anti-tumour responses to oncolytic viruses emphasise the clin-ical need for better stratification of cancer patients for viro-immunotherapy by selecting the most promising candidate OV in future clinical trials.
Developing oncolytic viruses for clinical use: a consortium approach To rapidly develop and implement viro-immunotherapy as a treatment modality for cancer, multiple academic institutions collaborate in the Dutch Oncolytic ViroImmuno Therapy consortium (OVIT). The OVIT consortium consists of multidisciplinary team of researchers and clinicians of three Dutch universities that are experts in virology, cancer immunology, (uro) oncology and surgery. [41] The major aim of the OVIT consortium is to develop an effi-cacious, safe and affordable viro-immunotherapy for patients with pancreatic, urothelial or glioblastoma tumours using promising oncolytic viruses from the participating groups, i.e., optimised Adenovirus, mammalian Reovirus and Newcastle disease virus strains.
Our data show that the variable responses to OV therapy is related to the susceptibility of the tumour cells to virus-induced oncolysis and the efficiency with which the immune sys-tem is activated upon OV infection of the tumour. Considering the variety of OVs, the multi-tude of genomic modifications in tumours and the diversity of tumour microenvironment immune landscapes, there is a clear need for platforms with predictive potential. modification leading to the identification of a promising, spontaneous jin-3 mutant Reovirus. [42,43]
Furthermore, we recently isolated and identified a novel, promising candidate non-human primate Adenovirus (NHP-AdV007) with strong oncolytic properties across multiple human tumour cell lines.[44,45] Non-human primate-derived adenoviruses form a valuable alter-native for the use of human adenoviruses in vaccine development and gene therapy strate-gies by virtue of the low seroprevalence of neutralising immunity in the human popula-tion.[44,45]
Selected Adenovirus and Reovirus strains display oncolytic properties in human PCa and BCa cell lines and ex vivo-cultured, patient-derived tumour tissues.[43] Moreover, the tested viruses induce multiple mediators of immunogenic cell death and immunostimulatory genes, but responses vary among the used OV and tumour combinations.[43] The latter observations highlight the importance of OV-tumour matching, hence a more personalised approach.
Combination therapy with oncolytic viruses Various clinical trials have demonstrated that oncolytic, replication-competent mammalian reoviruses and human adenoviruses are safe for patients and can display antitumour effica-cy in a variety of malignancies. Full responses of these monotherapeutic approaches, how-ever, were found in only a minority of patients. It is, therefore, crucial to understand how OVs can be exploited in combination with existing treatment modalities, i.e., chemotherapy and immunotherapy, to unleash their full potential.
Due to space constraints, the entire reference list can be made available to interested readers upon request by sending an email to: communications@uroweb.org.
Oncolytic viro-immunotherapy in urological cancers At the Leiden University Medical Center (LUMC), we have found that oncolytic potency of reoviruses in (urological) cancers can be enhanced by selection and genetic Friday, 1 July 08:00 - 10:15 Plenary Session 02 Grey Area, eURO Auditorium 2
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