TILT-123 – molecular profile of our lead product
TILT-123 is the result of years of engineering and testing of ten prototype oncolytic viruses in almost 300 patients in the Advanced Therapy Access Program (ATAP) at the University of Helsinki, Finland. It is optimized to generate an anti-cancer immune response by boosting the activity of T-cells and also stimulating other arms of the innate and adaptive immune system.
TILT-123 is a human 5/3 chimeric adenovirus that has been engineered for intravenous use, targeting, safety and potency.
Targeting, safety and route of administration
The viral construct includes double selectivity (E2F promoter and D24 deletion in the E1A gene), which means that replication and transgene production are only possible in cancer cells which are uncontrollably dividing and have a high expression of E2F. This is an important safety feature, ensuring that the therapeutic effect is targeted only at cancer cells.
TILT-123 can be administered by intravenous, intratumoral, intraperitoneal and intrapleural injection.
For Phase I results following intravenous delivery of TILT-123, see here.
This is how intratumoral injection works in practice:
Potency – armed with dual cytokines
The virus has been engineered to encode human Tumor Necrosis Factor alpha (hTNFa) and human Interleukin 2 (hIL-2) cytokines. It uses the cancer cell’s own machinery to replicate, produce both these cytokines in increased quantities. When the cancer cell lyses or ruptures, these cytokines are released into the tumor microenvironment, providing powerful alert signals for the immune system.
In this ‘decloaking’ process, T cells from the therapy or T cells from the patient’s immune system traffic to the tumor microenvironment, turning ‘cold’ tumors ‘hot’. The arrival of antitumor cell populations at the tumour with immunostimulatory signals triggers cancer cell killing and positive feedback on adaptive immunity against cancer.
TILT-123 viral construct
TILT is also investigating the ability to strengthen other cancer immunotherapy modalities by arming its oncolytic adenoviruses with other immunostimulatory ligands such as bispecific antibodies and other cytokines.
TILT-123 Mode of Action
TILT-123 – Clinical Development
TILT-123 is now in several clinical trials as monotherapy or in combination with cancer immunotherapies in Europe and the USA following successful completion of Phase Ia trials and treatment of over 50 patients. Read more
Phase I data published so far demonstrates good safety, preliminary signs of efficacy and disease control. In various pre-clinical in vivo models of aggressive cancer treated with TILT-123, our lead product or its mouse variants, a 100% response rate has been observed (Read more >). This data provides a solid foundation for advancing TILT-123 towards a Phase II trial for the treatment of ovarian cancer.
TILT’s armed oncolytic virus approach has the potential to be efficacious in the treatment of solid tumors refractory to other modalities. In contrast with other immunotherapies, which may trigger autoimmune responses, oncolytic adenoviruses have a strong safety profile. TILT-123 could help to increase antitumor efficacy of other immunotherapies without ‘adding-up’ on other toxicities.
Pipeline
We have multiple best-in-class oncolytic viral therapies in our pipeline, our lead therapeutic asset, TILT-123, is a cytokine armed oncolytic adenovirus that is currently in Phase 1 clinical trials in combination with tumor infiltrating lymphocytes (TIL) therapy in Europe.
Publications
Professor Hemminki has authored nearly 300 peer-reviewed manuscripts or book chapters on cancer research and oncolytic viruses.
