35P - Combination immunotherapy with oncolytic adenovirus and adoptive T-cell transfer leads to systemic anti-tumor immunity and enhanced therapeutic effi...

Date 20 November 2015
Event ESMO Symposium on Immuno-Oncology 2015
Session Welcome reception and general Poster viewing
Topics Cancer Immunology and Immunotherapy
Melanoma and other Skin Tumours
Translational Research
Presenter Siri Tähtinen
Citation Annals of Oncology (2015) 26 (suppl_8): 5-14. 10.1093/annonc/mdv514
Authors S. Tähtinen1, S. Grönberg-Vähä-Koskela2, D. Lumen3, M. Merisalo-Soikkeli2, M. Siurala4, A.J. Airaksinen3, M. Vähä-Koskela2, A. Hemminki4
  • 1Cancer Gene Therapy Group, Medicum, Haartman Institute, University of Helsinki, 00290 - Helsinki/FI
  • 2Department Of Pathology, University of Helsinki, Helsinki/FI
  • 3Department Of Chemistry, University of Helsinki, Helsinki/FI
  • 4Tilt Biotherapeutics Ltd, TILT Biotherapeutics Ltd, 00290 - Helsinki/FI

Abstract

Aim

Adoptive T-cell therapy (ACT) using genetically modified T-cells have shown exceptional efficacy in the treatment of CD19-expressing hematological malignancies, but efficacy in solid tumors has remained poor due to several immune evasion mechanisms. Oncolytic adenoviruses are conditionally replicating, cancer-specific viruses that are intrinsically immunogenic.

Methods

We tested if oncolytic adenovirus could break tumor-associated tolerance to T-cells in a highly resistant B16.OVA murine melanoma model.

Results

Following adoptive transfer of OVA-specific OT-I lymphocytes, control of B16.OVA tumor growth was superior in adenovirus treated immunocompetent C57BL/6 mice compared to control mice, even in the absence of active oncolysis. Significant increase in tumor-infiltrating CD45+, CD8+ and F4/80+ immune cells was seen Ad-treated tumors, suggesting enhanced tumor immunogenicity. Surprisingly, no statistically significant difference in numbers of tumor-infiltrating OT-I cells was detected between treatment groups. Instead, intratumoral administration of adenovirus induced maturation of professional CD11c+ antigen-presenting cells both in tumors and in tumor-draining lymph nodes. Subsequently, increased number of activated tumor-infiltrating CD8+ T-cells (TILs) was detected in Ad-treated mice, suggesting that tumor-induced T-cell hypofunction was overcome. Finally, an increase in endogenous CD8+ TILs specific for melanoma-associated antigens TRP-2 and gp100 was detected in combination treated mice, indicating repertoire expansion following immunotherapy. Majority of these combination treated mice rejected the re-challenge of parental B16.F10 tumors, suggesting that systemic, endogenous anti-tumor immunity was induced despite local (intratumoral) injection of adenovirus.

Conclusions

In conclusion, combining ACT with oncolytic adenovirus can break both local immunosuppression and peripheral tolerance of tumor-specific T-cells. Importantly, these two modalities are not merely an attractive combination, but could represent a way to achieve “CD19-like” results in the treatment of solid tumors.

Clinical trial identification

Disclosure

M. Siurala: Is employee in TILT Biotherapeutics Ltd. A. Hemminki: Is shareholder of Oncos Therapeutics, Ltd. and is employee in and shareholder of TILT Biotherapeutics Ltd. All other authors have declared no conflicts of interest.