Building a New Arsenal of Therapeutics from Oncolytic Viruses

TILT Biotherapeutics (TILT) is a Finland-based private biotechnology spin-out from the University of Finland focusing on the development of cancer immunotherapies utilizing oncolytic viruses encoded with a variety of cytokines to treat various cancers. The company was founded in 2013 by Akseli Hemminki, a cancer clinician, and aims to use an oncolytic virus to enhance T-cell therapy, including tumour-infiltrating lymphocytes (TILs), chimeric antigen receptor T cells (CAR-Ts), and checkpoint inhibiting antibody therapy of solid tumours (1).

Technology

The therapeutic benefit of various oncolytic viruses has been widely published in the literature, and researchers have improved the efficacy of first-generation products using genetic engineering (2). TILT coordinated a European Union (EU)-funded project, UNLEASHAD, which has developed an adenovirus-based oncolytic product, TILT-123 (igrelimogene litadenorepvec), that specifically targets and lyses cancer cells. It also releases TNF-α and interleukin-2 (IL-2) cytokines into the microenvironment, providing an alert and attracting immune cells to the tumour. This strategy ensures anti-tumour immunity and may be suitable for tumours that are refractory to other types of immunotherapies (3).

TILT-123 is currently in Phase I clinical trials as monotherapy and in combination with TIL therapy in Europe in metastatic melanoma. Preclinical results have been published, and the virus backbone has been demonstrated to be safe and well-tolerated in humans. Trials for other solid tumour indications are planned in combination with TILT-123 and a checkpoint modulator or a CAR-T product (2), and the company has other patent-protected products in the pipeline, including oncolytic viruses coding for bispecific antibodies TILT-321 and TILT-322 (3).

In May 2023, the company announced that the first patient had been dosed in a Phase I solid tumour trial, which will assess TILT-123 in combination with avelumab in squamous cell carcinoma of the head and neck (SCCHN) and melanoma in patients with advanced solid tumours refractory to, or progressing after, anti-programmed cell death ligand 1 (anti-PD-L1) (4). The study is part of TILT’s agreement with Merck KGaA, Darmstadt, Germany, and Pfizer, and the European trial is underway at the Docrates Cancer Center (Helsinki, Finland). The company expects to open its US site in the third quarter of 2023 (5). In November 2022, TILT opened an office in Boston to support its US clinical trial programme.

According to CEO Aseli Hemminki, “The oncolytic virus is designed with T cells in mind, and this design is based on patient observations, not just laboratory data. TILT-123 is armed with the most potent cytokines in the context of adaptive anti-tumour responses; it is genetically modified for improved access to cancer cells and for improved safety. Moreover, adenovirus is the most immunogenic virus type and is possible to upscale in manufacturing for industrial production. Importantly, TILT’s virus backbone has already been demonstrated safe in humans and can access distant tumours by vascular route. Therefore, in addition to intratumoural administration, the product can be administered by systemic route” (1).

Partnerships

TILT has partnered with Germany-based Merck KGaA, Switzerland-based MSD International GmbH, and US-based Pfizer (Merck-Pfizer Alliance). TILT is collaborating with the Cancer Gene Therapy Group at the University of Helsinki and with the University of Pennsylvania, where they are exploring the use of TILT‑123 in combination with CAR-Ts in solid tumours (6).

Investor funding

Since its conception, TILT has attracted more than US$42 million (€39 million) in private investment. On 7 Feb. 2023, it raised €22 million (US$23.8 million) from a financing round led by Finland’s Lifeline Ventures and €5.9 million (US$6 million) equity from the European Innovation Council (EIC) Fund as well as a €2.1 million (US$2.3 million) grant from EIC’s Accelerator programme. In addition, the company has received investments from Stephen Industries Inc Oy and ACME Investments SPF Sàrl. These funds will be used to advance the development of TILT-123 to Phase II clinical trials (7). This follows on from the first funding round of €10 million (US$10.9 million) in June 2022.

Competitor companies

There is significant interest in TIL‑based therapeutics, and several companies both in Europe and the United States are exploring this route. In the US, TIL-based therapies are under development from: CTRL Therapeutics (8), Iovance Biotherapeutics (9), Obsidian Therapeutics (10), and Turnstone Biologics (11). Recently, Concerta Bioscience acquired Jounce Therapeutic to gain access to its first-in-class immunotherapy, which is designed to selectively deplete immunosuppressive tumour-infiltrating T regulatory cells in the tumour microenvironment (12).

The future of TILT

Over the past few years, R&D efforts in the field of oncolytic viruses have received support from private investors and pharmaceutical companies. TILT’s leading programme, TILT-123, is progressing steadily through Phase I clinical development, and the company has raised sufficient funds to progress into Phase II trials. However, competition within this field is increasing as Concerta Biosciences, CTRL Therapeutics, and Obsidian Therapeutics have pre‑clinical candidates, and Turnstone Biologics has two Phase I trials underway with TILs. Meanwhile, Iovance Biotherapeutics has several Phase II trials nearing completion that are evaluating TILs as monotherapy and in combination with PD-1 or IL-2 analogues. Therefore, investors will be keen to see updates on TILT’s Phase II trial (NCT04217473), which is due for completion in February 2025 (13), and will be closely monitoring other competitor products as they progress through clinical development.

References

1. Hemminki, A. TILT Biotherapeutics. Hum. Vaccin. Immunother. 2017 13 (5), 970–971.
2. TILT Biotherapeutics. Next-generation Armed Oncolytic Immunotherapies. Biopharm. Deal. May 2022.
3. EC. New Immunotherapy Tools to Fight Cancer. UNLEASHAD Project. Results in brief. H2020. CORDIS. 1 July 2018.
4. TILT Biotherapeutics. TILT Biotherapeutics Announces First Patient Dosed in Phase I Solid Tumours. Press Release, 15 May 2023.
5. TILT Biotherapeutics. TILT Biotherapeutics Announces Boston Office Opening as it Expands its Clinical Trials in the US. Press Release, 11 Sep. 2022.
6. TILT Biotherapeutics. Pipeline. TILTbio.com (accessed 17 Aug. 2023).
7. TILT Biotherapeutics. TILT Biotherapeutics Announces Final Close of €22 Million Financing. Press Release, 7 Feb. 2023.
8. cTRL Therapeutics. Accessible Cell Therapy (accessed 17 Aug. 2023).
9. Iovance Biotherapeutics, Investigating TIL Therapy & PBL Therapy for Cancer (accessed 17 Aug. 2023).
10. Obsidian Therapeutics. Our Lead Clinical Program (accessed 17 Aug. 2023).
11. Turnstone Biologics. Leading the Fight Against Solid Tumours (accessed 17 Aug. 2023).
12. Jounce Therapeutics. Jounce Therapeutics Enters Into an Agreement to Be Acquired by Concentra Biosciences for $1.85 in Cash per Share Plus Contingent Value Rights. Press Release, 27 Mar. 2023.
13. A Phase 1, Open-Label, Dose-Escalation Clinical Trial of Tumour Necrosis Factor Alpha and Interleukin 2 Coding Oncolytic Adenovirus TILT‑123 in Melanoma Patients Receiving Adoptive Cell Therapy With Tumour Infiltrating Lymphocytes. classic.clinicaltrials.gov/ct2/show/NCT04217473 (accessed 17 Aug. 2023).

About the author

Cheryl Barton is director of Pharmavision, info@pharmavision.co.uk.