61P - Arming oncolytic adenovirus with FAP-targeting Bispecific T-cell Engager to improve antitumor efficacy (61P)

Date 08 December 2017
Event ESMO Immuno-Oncology Congress 2017
Session Lunch & Poster Display session
Topics Non-Small-Cell Lung Cancer, Early Stage
Lung and other Thoracic Tumours
Presenter Jana de Sostoa Pomés
Citation Annals of Oncology (2017) 28 (suppl_11): xi6-xi29. 10.1093/annonc/mdx711
Authors J. de Sostoa Pomés, C.A. Fajardo, M. Farrera Sal, R. Moreno, M. Arias-Badia, L.A. Rojas, R. Alemany
  • Procure, Bellvitge Biomedical Research Institute (IDIBELL) - Hospital Duran i Reynals, 08908 - Hospitalet de Llobregat/ES

Abstract

Background

Oncolytic adenovirus (OAd) -based therapies face various challenges that may weaken their efficacy. Generating OAd arming FAP-targeting BiTE might improve antitumor efficacy by re-directing T-cells to kill stroma.

Methods

FAP-BiTE (FBiTE) comprises two single chain variable fragments (ScFvs) joined by a flexible Gly-Ser linker. One scFv arm binds human CD3epsilon on the T cell receptor (TCR), while the other binds mouse and human Fibroblast Activation Protein (m/hFAP). The FBiTE gene was incorporated by recombineering in bacteria into the OAd (ICO15K) genome under two different splice acceptors: IIIa and 40SA. The OAds obtained were amplified and purified. HT1080 and 293 FAP- and m/hFAP+ cell lines were used for the in vitro experiments, and A549 cell line and NSG mice for in vivo experiments.

Results

OAds ICO15K-IIIa-FBiTE and ICO15K-40SA-FBiTE were properly generated. Both viruses conserved their cytotoxic properties compared to the parental virus ICO15K and had the capability to infect specifically the tumour cells. FBiTEs were synthesised by the infected cells and secreted to the extracellular media. In vitro, the FBiTE molecules bound simultaneously to FAP+ and CD3+ cells, inducing a catalytic immunological synapsis. This reaction provoked the activation and proliferation of the T-cells specifically against FAP+ cells, inducing significantly more cytotoxicity compared to the parental virus. Moreover, ICO15K-FBiTE in combination with preactivated human T-cells enhanced antitumor efficacy in vivo.

Conclusions

We generated an OAds expressing FAP-targeting BiTE which is expressed and secreted from infected cells. These FBiTEs are able to activate and re-direct T-cells to FAP+ cells, which leads to enhance cytotoxicity in vitro and improve antitumor efficacy in vivo. Further in vivo studies are underway in additional tumour models.

Clinical trial identification

Legal entity responsible for the study

Virotherapy and Immunotherapy group

Funding

MINECO

Disclosure

All authors have declared no conflicts of interest.