2PD - Oncolytic adenoviruses armed with TNFα and IL-2 enable successful adoptive T-cell therapy of solid tumors

Date 20 November 2015
Event ESMO Symposium on Immuno-Oncology 2015
Session Poster Discussion session
Topics Cancer Immunology and Immunotherapy
Presenter Suvi Parviainen
Citation Annals of Oncology (2015) 26 (suppl_8): 1-4. 10.1093/annonc/mdv513
Authors S. Parviainen1, R. Havunen2, M. Siurala1, S. Tähtinen2, D. Saha2, M. Vähä-Koskela2, M. Behr2, D. Nettelbeck3, A. Ehrhardt4, A. Hemminki1
  • 1Tilt Biotherapeutics Ltd, TILT Biotherapeutics Ltd, 00290 - Helsinki/FI
  • 2Cancer Gene Therapy Group, Medicum, Haartman Institute, University of Helsinki, 00290 - Helsinki/FI
  • 3Oncolytic Adenovirus Group, German Cancer Research Center, Heidelberg/DE
  • 4Fakultät Für Gesundheit, Witten/Herdecke University, Witte/DE

Abstract

Aim

Although adoptive T-cell therapy has yielded promising results especially in chimeric antigen receptor (CAR) therapy of CD19+ hematological tumors, efficacy in solid tumors has been modest. Major bottlenecks for anti-tumor effects are T-cell tolerance and the immunosuppressive tumor microenvironment, preventing efficient recruitment of T cells into tumors. Therefore, a major hurdle that has to be overcome in order for cancer immunotherapy to reach its full clinical potential is to neutralize immune suppressive conditions in the tumor microenvironment. We propose to use oncolytic adenoviruses coding for immunostimulatory cytokines interleukin 2 (IL-2) and Tumor Necrosis Factor alpha (TNFα) to make T-cell therapy work in solid tumors. The danger signal caused by virus replication, coupled with the actions of the transgene and effective presentation of tumor epitopes by lysis of the cells, could result in a personalized cancer vaccine. Notably, these cytokines can cause severe side effects when administered systemically, however these problems could be solved by local production at the tumor by a viral vector.

Methods

We have developed and characterized oncolytic adenoviruses expressing one or both above mentioned human cytokines (Ad5/3-E2F-D24-hTNFα, Ad5/3-E2F-D24-hIL2 and Ad5/3-E2F-D24-hTNFα-IRES-hIL2). For immune competent murine studies we constructed non-replicative adenoviruses with murine cytokines (Ad5-CMV-mIL2 and Ad5-CMV-mTNFα). Virus injections were given in combination with intraperitoneal adoptive transfer of OT-1 TCR transgenic T-cells to treat C57BL/6 mice bearing B16-OVA melanoma tumors.

Results

Combination treatment with Ad5-CMV-mIL2 and OT-1 resulted in statistically significant antitumor efficacy when compared with either monotherapy or untreated control. In further experiments a triple combination of Ad5-CMV-mIL2 + Ad5-CMV-mTNFa and OT-1 T-cells improved antitumor efficacy was observed over dual agent therapies.

Conclusions

In conclusion, these results provide a strong rationale for combining cytokine-armed adenoviruses with T-cell therapy regimens.

Clinical trial identification

Disclosure

S. Parviainen: Is an employee of TILT Biotherapeutics Ltd. M. Siurala: Is an employee and stock option holder at TILT Biotherapeutics Ltd. A. Hemminki: Is CEO at TILT Biotherapeutics Ltd., reports receiving a commercial research grant from Oncos Therapeutics, and has ownership interest (including patents) in TILT Biotherapeutics and Oncos Therapeutics. All other authors have declared no conflicts of interest.