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Viruses, Immune stimulation and RNA Interference in Oncology Network

Periodic Reporting for period 2 - VIRION (Viruses, Immune stimulation and RNA Interference in Oncology Network)

Reporting period: 2017-10-01 to 2019-09-30

The Viruses, Immune stimulation and RNA Interference in Oncology Network (VIRION) is focused on the development of a novel therapeutic regime by combining immune therapy with oncolytic virotherapy and RNA interference techniques.

Recent clinical successes have shown the immune system to be a powerful ally in the fight against cancer. While surgery, chemotherapy and radiation therapy remain the first lines of treatment for most tumors, immunotherapy regimens are achieving astonishing clinical successes. Furthermore, recent studies showed that pre-existing lymphocytic infiltration of tumors is associated with superior prognostic outcomes in a variety of cancers and might improve cancer therapies targeting immune checkpoints. A new development in the immunotherapy field is adoptive cell therapy (ACT). In ACT, lymphocytes from cancer patients are expanded ex vivo into more favorable numbers; often modified genetically or stimulated to relieve immune suppression; and infused back into the patient. In clinical trials, ACT has resulted in anti-tumor responses.

However, immune suppression in the tumor microenvironment limits the efficacy of immunotherapy and remains a major hurdle. Therefore, we aim to potentiate the antitumor immune reaction in the tumor microenvironment, through the combination of immune therapy and oncolytic virotherapy. Oncolytic viruses are developed to specifically target and destroy tumor cells. In pre-clinical models, oncolytic adenoviruses have proven a powerful tool in the elimination of tumors, not only by their direct lytic effects but also by their triggering of a subsequent tumor inflammation and enhanced lymphocytic infiltration. VIRION addresses how these immune responses can be further enhanced by addition of immune modulating factors and/or siRNA targeting cancer genes that play a role in immune suppression.

Our studies have demonstrated that oncolytic adenovirus are able to modulate the tumor micro-environment by themselves resulting in increased immune activity. This can be further enhanced by checkpoint blockers (anti-PD1 or anti-PDL1) and adoptive cell therapy. Although these latter elements by themselves have impact on the tumor microenvironment and stimulate anti-tumor responses, combining these with oncolytic adenovirus results in a further enhancing of the anti-tumor immune response. In addition different siRNA targets and modulating genes have been identified which will can give rise to a new generation of oncolytic adenoviruses with enhanced potency and abilities to induce anti-tumor immune responses.
Five ESR were recruited from four different European countries. Besides receiving training in working in academic and pharmaceutical environments, the ESRs received biobusiness workshops, enhanced interaction with partners to expose them other disciplines (regulatory, quality, CMC, patent law).

The ESRs developed novel screening platforms that allowed for high throughput screening of compounds, siRNA and shRNA. Co-culturing methods that were developed that allowed studies of the tumor immune micro environment in vitro and the impact of immune modulators and oncolytic adenoviruses. This platform facilitated screening of compounds and elucidation of impact of combinations on the tumor immune micro environment. The in vitro studies were followed up with in vivo studies in demonstrating the synergism of oncolytic adenovirus with checkpoint blockers and/or adoptive cell transfer.

The results of the program were published on the consortium website (VIRION) and beneficiaries website. In addition, the results were presented at 27 international conferences. The ESRs were awarded 11 oral presentations and 16 poster presentations. Furthermore the ESRs have published their work in 13 publications in peer reviewed journals, with 6 more publications in preparation or submitted.

Overview primary conclusions:
- Identification of a gene that enhances oncolytic potency and immune-activation; ORCA therapeutics will work together with the VUmc to further develop this technology.
- Identification of genes that can be silenced using siRNA in order to enhance immune activation; VUmc will further develop the leads obtained.
- Studies with ACT and immune check point blockers provided supportive data for further development and progression into the clinical phase; TILT is preparing clinical trials to confirm the preclinical data.
- Studies performed at ORCA and TILT demonstrated the synergism between oncolytic virus and check-point blockers; TILT and ORCA are planning clinical trials combining oncolytic virus with checkpoint blockers.
Our results demonstrated that combining oncolytic adenoviruses with check-point blockers result in activation of immune cells in vitro, enhanced anti-tumor immune responses and prolonged survival in vivo. Furthermore we demonstrated that pre- and postconditioning regimens have high clinical relevance and the potential to significantly impact the lives of cancer patients going through adoptive T cell therapies. Also, the preclinical studies performed with checkpoint inhibitor immunotherapy provide the rationale for a clinical clinical where oncolytic adenovirus is used in melanoma patients receiving an anti-PD-1 antibody, potentially improving cure rates significantly.

Future studies will focus on the optimization of the dosing schedule for adenovirus and checkpoint inhibitor, and investigating the biological mechanism-of-action behind the observed improvement in antitumor efficacy. In addition, the effect of adenovirus-derived cytokines on immune cell subsets relevant to cancer will be studied. We expect to gain knowledge of the potential of the aforementioned cytokines to modify cancer-related immune cells to a more favourable direction.
VIRION team at ECI congres (posters and talk)
The VIRION Consortium - 2017
I Milenova receives ESGCT award
VIRION Final meeting