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Abstract
Background The deployment of immunotherapies in the forefront of cancer therapy fundamentally changed patient care and the understanding of tumor immunology. In contrast to more conventional therapies, immune checkpoint inhibitors (ICIs) and adoptive cell therapies (ACTs), are characterized by durable responses in the treatment of metastatic cancer. However, such clinical benefits account only for a portion of treated patients, leaving room for improvement or generation of new immunotherapy strategies. TILT-123 (also known as Ad5/3-E2F-d24-hTNFa-IRES-hIL2), is an oncolytic adenovirus encoding for tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2), that primarily bolsters antitumor immunity through T cells, and is capable of enhancing clinically-relevant immunotherapy approaches.1–4 Clinical development is ongoing across four different international open-label phase I clinical trials enrolling patients with refractory or recurrent solid tumors that cannot be treated with available therapies, such as advanced melanoma, head and neck cancer and ovarian cancer. Patients are receiving TILT-123 alone (TUNIMO, NCT04695327), and in combination with adoptively transferred tumor-infiltrating lymphocytes without pre- or post-conditioning (TUNINTIL, NCT04217473) or ICIs (PROTA, NCT05271318; AVENTIL, NCT05222932).
Methods The primary aim of these ongoing phase I clinical studies is to dissect the safety profile of escalating doses of the therapy in patients bearing refractory or recurrent solid tumors, via the observation of adverse events, laboratory values, vital signs, and electrocardiogram. Tumor response (based on RECIST 1.1/iRECIST/PET criteria), biosafety, pharmacological studies in patient samples, among others, are secondary endpoints. These will serve to unravel the mechanism of action of the therapy in the patients. TILT-123 is administered intravenously and intratumorally and patients are required to have an injectable tumor to receive treatment.
Results Combined interim safety data analysis demonstrate that TILT-123 therapy is well-tolerated at the dose levels tested – no treatment related serious adverse events or dose-limiting toxicities were observed. The most prevalent adverse events observed (based on CTCAE v5.0) were low grade fatigue, chills, pyrexia and nausea. Antitumor activity of TILT-123 by RECIST1.1/iRECIST criteria has been detected in patients through conventional CT and PET imaging. Pharmacokinetics, biosafety as well as biological correlates are being studied.
Conclusions Accumulating evidence indicates that TILT-123 with immunotherapy is safe and shows signs of antitumor activity, thus endorsing further clinical development.
Acknowledgements We thank the site staff, the patients and their families, and all the academic and industry collaborators for their critical contributions to the studies described. These studies are funded by TILT Biotherapeutics Ltd.
Trial Registration TUNIMO trial - NCT04695327 TUNINTIL trial - NCT04217473 PROTA trial -NCT05271318 AVENTIL trial - NCT05222932
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Ethics Approval Informed consent was obtained from all patients before participation in the clinical trials. TUNIMO trial - This study was approved by the Finnish National Committee on Medical Research Ethics (TUKIJA); approval number HUS/1804/2020 TUNINTIL trial - This study was approved by the Danish National Committee on Health Research Ethics (NVK); approval number 1905760 PROTA trial - This study was approved by the Finnish National Committee on Medical Research Ethics (TUKIJA); approval number TUKIJA/405/2021 AVENTIL trial - This study was approved by This study was approved by the Finnish National Committee on Medical Research Ethics (TUKIJA); approval number TUKIJA/366/2021
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