igrelimogene litadenorepvec (TILT-123)

P1, N=22, Recruiting, TILT Biotherapeutics Ltd. | Trial completion date: Oct 2025 --> May 2026 | Trial primary completion date: Oct 2024 --> Jan 2026

TILT-123 demonstrated safety and significant intratumoral immunomodulation following a single i.v. administration, warranting further investigation.

P1, N=29, Recruiting, TILT Biotherapeutics Ltd. | Trial completion date: Mar 2026 --> Jan 2027 | Trial primary completion date: Jun 2024 --> Jan 2025

TILT-123 was safe and able to produce anti-tumor effects in local and distant lesions in heavily pre-treated patients. Good tolerability of TILT-123 facilitates combination studies, several of which are ongoing (NCT04217473, NCT05271318, NCT05222932, NCT06125197).

P1, N=22, Recruiting, TILT Biotherapeutics Ltd. | Not yet recruiting --> Recruiting | Initiation date: Nov 2023 --> Mar 2024

P1, N=17, Active, not recruiting, TILT Biotherapeutics Ltd. | Recruiting --> Active, not recruiting | Trial primary completion date: May 2023 --> Dec 2023

P1, N=18, Recruiting, TILT Biotherapeutics Ltd. | Trial primary completion date: Dec 2023 --> Sep 2024

P1, N=22, Not yet recruiting, TILT Biotherapeutics Ltd.

A detailed immunological profile will be presented. Conclusions Treatment with TILT-123 oncolytic adenovirus changes the profile of immune cells circulating systemically and locally infiltrating injected and non-injected tumor sites.

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.

TILT-123), a serotype chimeric oncolytic adenovirus armed with tumor necrosis factor alpha (hTNFα) and interleukin 2 (hIL-2), administered intravenously...Conclusions Our findings highlight the potential of intravenously delivered oncolytic adenovirus armed with hTNFα and hIL-2 in combination with aPD-1 checkpoint blockade to overcome checkpoint resistance and improve treatment outcomes in advanced NSCLC. This approach is promising for addressing the major unmet clinical need in patients with checkpoint refractory/resistant NSCLC and supports further investigation in clinical trials.

Thus, we complemented our findings using NSCLC ex vivo models fully permissive for the TNFα and IL-2- armed oncolytic adenovirus TILT-123. Overall, our data demonstrate the ability of systemically administered adenovirus armed with TNFα and IL-2 to potentiate the anti-tumor efficacy of aPD-1 and warrant further investigation in clinical trials.

Since 2020, four Phase I studies have been initiated: a monotherapy (NCT04695327) and combinations with TILs (NCT04217473), pembrolizumab or avelumab (NCT05271318, NCT05222932). Likewise, analysis of tumor samples revealed increasing diversity of CD8 and CD4 T lymphocyte subsets.Emerging data from clinical trials suggests that TILT-123 has an adequate safety profile and can reshape the tumor microenvironment resulting in antitumor activity, at the tested doses. Studying biological samples allowed a better understanding on the mechanism of action of this gene therapy product.

P1, N=15, Recruiting, TILT Biotherapeutics Ltd. | Trial primary completion date: Oct 2023 --> May 2023

P1, N=15, Recruiting, TILT Biotherapeutics Ltd. | Trial primary completion date: Oct 2022 --> Oct 2023

Supernatants from hybridoma parent subclone 11B12B4 provided the highest positive PD-L1 signal, on Syrian hamster PBMCs and three cancer cell lines (HT100, HapT1 and HCPC1). Novel Syrian hamster anti-PD-L1 clone 11B12-1 induces tumour growth control in a hamster model of PDAC. Combining 11B12-1 with oncolytic adenovirus TILT-123 improves tumour growth control further and demonstrates good safety and toxicity profiles.

Immunological data (e.g. flow cytometry and/or cytokine data) will be presented. Conclusions TILT-123 can induce systemic immunological effects supporting the continued development of the agent as cancer immunotherapy.

Background After the first Immune Checkpoint Inhibitor (ICI) was approved (ipilimumab, 2011 for cancer therapy, the list of indications routinely treated with ICIs keeps increasing. Conclusions Preliminary data emerging from Phase I clinical trials using TILT-123, point to an adequately safe approach able to induce antitumor activity, both as monotherapy and in combination. Dose escalation continues in pursuit of a recommended dose to use in Phase II clinical trials.

All the process and product-related impurities were within the specification range required by the regulatory authorities. The technology transfer run was used to supply biodistribution and toxicity studies, the Engineering run is currently being used for quality control development and as reference material, while GMP manufacturing campaigns are being used to supply a clinical trial.

TILT-123 is an oncolytic adenovirus (Ad5/3-E2F-D24-TNFa-IRES-IL2) designed to enable T-cell therapies and checkpoint inhibition against cancer...Cohorts 1-3 have been completed without DLTs. Enrollment in cohort 4 was initiated in December 2021.

P1, N=15, Recruiting, TILT Biotherapeutics Ltd. | Trial completion date: May 2022 --> Dec 2024 | Trial primary completion date: Jan 2022 --> Oct 2022

P1, N=15, Recruiting, TILT Biotherapeutics Ltd. | Trial completion date: Jul 2021 --> May 2022 | Trial primary completion date: May 2021 --> Jan 2022

. Secondary endpoints include evaluation of safety and tolerability for the duration of the trial, antitumor efficacy, antitumor responses, and biological effects against tumors. Enrollment began in 2020 and, at the time of submission, cohort 1 was completed without DLTs, and cohort 2 enrolment is in progress.

The virus is rapidly cleared from healthy tissues, and it does not cause damage to vital organs. The results support the initiation of a phase 1 dose-escalation trial, where melanoma patients receiving a tumor-infiltrating lymphocyte therapy are treated with TILT-123 (NCT04217473).

Overall, oncolytic adenovirus Ad5/3-E2F-D24-hTNFa-IRES-hIL2 was able to rewire the ovarian tumor microenvironment to accommodate heightened antitumor TIL reactivity. Such effects may improve the clinical effectiveness of ACT with TILs in patients with advanced OVCA.

When Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (an oncolytic adenovirus coding for TNFa and IL-2, also known as TILT-123) and checkpoint inhibitors were used together in fresh urological tumor histocultures, a significant shift toward immune activity (not only tumor necrosis alpha and interleukin-2 but also interferon gamma and granzyme B) and increased T-cell trafficking signals (CXCL10) was observed...To conclude, when an engineered oncolytic adenovirus was utilized to modify the tumor microenvironment towards what meta-analyses have pointed as predictive markers for checkpoint inhibitory therapy, the response to them increased synergistically. Of note, key findings were confirmed in fresh patient-derived tumor explants.

P1, N=15, Recruiting, TILT Biotherapeutics Ltd. | Not yet recruiting --> Recruiting

Hence, we hypothesized that an oncolytic adenovirus expressing Tumour Necrosis Factor (TNF)-alpha(a) and Interleukin (IL)-2 (Ad5/3-E2F-D24-hIL-2-IRES-TNFa; TILT-123) could overcome this by generating a proinflammatory microenvironment and reinvigorating TIL anti-tumour activity... These data illustrate the potential of oncolytic adenovirus coding for TNFa and IL-2 to rewire the ovarian tumour microenvironment for effective TIL anti-tumour reactivity. This approach may improve the efficacy of adoptive TIL therapy in ovarian cancer patients, thus warranting further clinical investigation.Legal entity responsible for the study: TILT Biotherapeutics Ltd. Funding: TILT Biotherapeutics Ltd.