54P - T-cell therapy – enabling oncolytic adenoviruses for the treatment of melanoma (54P)

Abstract

Background

Adoptive cell transfer (ACT) has shown promising yet suboptimal results in clinical trials for melanoma. We aimed to enhance the efficacy of ACT by coupling it with adenoviruses coding for tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2).

Methods

Non-replicating adenoviruses (Ad5-CMV-mIL2 and Ad5-CMV-mTNFa) were constructed and confirmed to produce biologically active murine cytokines in vitro and in vivo, and subsequently used in combination with ovalbumin-specific (OT-I) T-cell transfer. Oncolytic adenoviruses expressing human TNFa and/or human IL-2 (Ad5/3-E2F-D24-hTNFa-IRES-hIL2 also known as TILT-123) were also constructed and used in combination with tumor-infiltrating lymphocytes (TIL) transfer in adenovirus-permissive Syrian hamsters.

Results

The non-replicating virus vectors used in combination with OT-I T-cells effectively controlled tumor growth of established murine melanoma (B16.OVA) tumors. In further experiments, a triple combination of Ad5-CMV-mIL2 + Ad5-CMV-mTNFa (1:1 ratio) and OT-I T-cells improved antitumor efficacy over double combinations. Mechanistic studies revealed that intratumoral virus injections induce trafficking of adoptively transferred T-cells to tumors. Further, the cytokine-coding adenoviruses caused favorable alterations in the tumor microenvironment. In hamsters, established pancreatic cancer tumors were eradicated with TILT-123 injections coupled with TIL transfer. The cured animals were protected from tumor rechallenge. In addition, we have demonstrated that adenovirally delivered IL-2 is superior to systemically administered recombinant IL-2 with regard to safety and efficacy in the preclinical setting.

Conclusions

The combinatorial approach studied here highlights the potential of adenovirotherapy to enable T-cell therapies. TILT Biotherapeutics is in the process of confirming the results in clinical trials.

Clinical trial identification

Legal entity responsible for the study

TILT Biotherapeutics Ltd

Funding

TILT Biotherapeutics Ltd, Finland; Jane and Aatos Erkko Foundation, Finland; European Commission Marie Curie Innovative Training Network (ITN) grant VIRION (H2020-MSCA-ITN-2014 project number 643130); Doctoral Program in Clinical Research, University of Helsinki, Finland; Helsinki University Central Hospital (HUCH) Research Funds, Finland; Sigrid Juselius Foundation, Finland; Biocentrum Helsinki, Finland; Biocenter Finland, Finland; Finnish Cancer Organizations, Finland.

Disclosure

J.M. Santos, M. Siurala, R. Havunen, V. Cervera-Carrascon, S. Sorsa: Employee in TILT Biotherapeutics Ltd. A. Hemminki: Shareholder of Targovax SA and employee in TILT Biotherapeutics Ltd.