66P - Replacing lymphodepleting preconditioning with an oncolytic adenovirus coding for tumor necrosis factor alpha and interleukin-2 in adoptive cell th...

Date 08 December 2017
Event ESMO Immuno-Oncology Congress 2017
Session Lunch & Poster Display session
Topics Anti-Cancer Agents & Biologic Therapy
Oesophageal Cancer
Gastrointestinal Cancers
Presenter João Manuel Santos
Citation Annals of Oncology (2017) 28 (suppl_11): xi6-xi29. 10.1093/annonc/mdx711
Authors J.M. Santos1, V. Cervera-Carrascon1, R. Havunen1, S. Zafar1, M. Siurala2, S. Sorsa2, M. Anttila3, A. Hemminki1
  • 1Department Of Oncology, University of Helsinki-Faculty of medicine, 00290 - Helsinki/FI
  • 2Tilt, TILT Biotherapeutics Ltd, 00290 - Helsinki/FI
  • 3Pathology Unit, Finnish Food Safety Authority, 00790 - Helsinki/FI

Abstract

Background

Lymphodepleting preconditioning is a standard method used to increase the clinical efficacy of adoptive cell therapy (ACT) of solid tumors using tumor-infiltrating lymphocytes (TILs) or gene-engineered T cells. While it boosts the antitumor efficacy of transferred T cells by, increasing the availability of supporting cytokines and reducing the immunosuppression in the tumor, systemic lymphodepleting preconditioning is highly toxic for patients. Conversely, oncolytic adenovirus therapy is well tolerated and, when designed to express tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2), can improve the potency of ACT by local immune modulation.

Methods

Here, we compare the safety and efficacy of an ACT protocol using, an adenovirus coding for TNFα and IL-2 or, a cyclophosphamide and fludarabine lymphodepleting regimen. Since hamsters allow us to study the oncolytic capability of a human adenovirus, we used a subcutaneous pancreatic tumor model (HapT1) in a syngeneic golden Syrian hamster infused with TILs. Moreover, to identify the immune cells responsive to the TNFa and IL-2, we used a non-replicating adenovirus in a subcutaneous melanoma model (B16.OVA) established in a syngeneic mouse infused with ovalbumin-specific T cells.

Results

Both models showed that adenovirus therapy or lymphodepleting preconditioning improve the efficacy and tumor control of ACT. Yet, in hamsters, lymphodepletion caused a decline in survival compared with adenovirus therapy. Flow cytometry analysis of mouse tumors from both therapies revealed, an upregulation of IL-2, TNFa and interferon gamma (IFNg) and, high infiltration of T cells (CD3+) and mature dendritic cells (CD11c+CD86+). Also, M2-like macrophages (CD11b+F4/80+CD206+) were markedly reduced in adenovirus therapy. Of note, and similar to humans, degeneration in the heart and lungs was observed in animals that received lymphodepleting chemotherapy. Toxicity was barely observed in adenovirus treated groups.

Conclusions

Overall, this data suggests that our oncolytic adenovirus can replace high dose preconditioning chemotherapy in conventional ACT protocols. This rationale will be further explored in a Phase I clinical trial.

Clinical trial identification

Legal entity responsible for the study

Cancer Gene Therapy Group, TILT Biotherapeutics Ltd

Funding

TILT Biotherapeutics Ltd

Disclosure

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

All other authors have declared no conflicts of interest.