Novel combinatorial therapy of oncolytic adenovirus AdV5/3-D24-ICOSL-CD40L with anti PD-1 exhibits enhanced anti-cancer efficacy through promotion of intratumoral T-cell infiltration and modulation of tumour microenvironment in mesothelioma mouse model

Mariangela Garofalo; Magdalena Wieczorek; Ines Anders; Monika Staniszewska; Michal Lazniewski; Marta Prygiel; Aleksandra Anna Zasada; Teresa Szczepińska; Dariusz Plewczynski; Stefano Salmaso; Paolo Caliceti; Vincenzo Cerullo; Ramon Alemany; Beate Rinner; Katarzyna Pancer; Lukasz Kuryk

doi:10.3389/fonc.2023.1259314

Novel combinatorial therapy of oncolytic adenovirus AdV5/3-D24-ICOSL-CD40L with anti PD-1 exhibits enhanced anti-cancer efficacy through promotion of intratumoral T-cell infiltration and modulation of tumour microenvironment in mesothelioma mouse model

Front Oncol. 2023 Nov 20:13:1259314. doi: 10.3389/fonc.2023.1259314. eCollection 2023.

Authors

Mariangela Garofalo¹, Magdalena Wieczorek², Ines Anders³, Monika Staniszewska⁴, Michal Lazniewski^{4

5}, Marta Prygiel⁶, Aleksandra Anna Zasada⁶, Teresa Szczepińska⁴, Dariusz Plewczynski^{7

8}, Stefano Salmaso¹, Paolo Caliceti¹, Vincenzo Cerullo^{9

10

11

12

13}, Ramon Alemany¹⁴, Beate Rinner³, Katarzyna Pancer², Lukasz Kuryk^{2

4

15}

Affiliations

¹ Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
² Department of Virology, National Institute of Public Health, National Institute of Hygiene (NIH) - National Research Institute, Warsaw, Poland.
³ Division of Biomedical Research, Medical University of Graz, Graz, Austria.
⁴ Centre for Advanced Materials and Technologies, Warsaw University of Technology, Warsaw, Poland.
⁵ Department of Bacteriology and Biocontamination Control, National Institute of Public Health, National Institute of Hygiene (NIH) - National Research Institute, Warsaw, Poland.
⁶ Departament of Sera and Vaccines Evaluation, National Institute of Public Health, National Institute of Hygiene (NIH) - National Research Institute, Warsaw, Poland.
⁷ Laboratory of Bioinformatics and Computational Genomics, Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland.
⁸ Laboratory of Functional and Structural Genomics, Centre of New Technologies, University of Warsaw, Warsaw, Poland.
⁹ Drug Research Program (DRP), ImmunoViroTherapy Lab (IVT), Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
¹⁰ Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
¹¹ Translational Immunology Program (TRIMM), Faculty of Medicine Helsinki University, University of Helsinki, Helsinki, Finland.
¹² Digital Precision Cancer Medicine Flagship (iCAN), University of Helsinki, Helsinki, Finland.
¹³ Department of Molecular Medicine and Medical Biotechnology and CEINGE, Naples University Federico II, Naples, Italy.
¹⁴ Oncobell Program of Bellvitge Biomedical Research Institute (IDIBELL), ProCure Program of Catalan Institute of Oncology (ICO), Avinguda de la Granvia de l'Hospitalet, L'Hospitalet de Llobrega, Barcelona, Spain.
¹⁵ Clinical Science, Valo Therapeutics, Helsinki, Finland.

Abstract

Introduction: Malignant mesothelioma is a rare and aggressive form of cancer. Despite improvements in cancer treatment, there are still no curative treatment modalities for advanced stage of the malignancy. The aim of this study was to evaluate the anti-tumor efficacy of a novel combinatorial therapy combining AdV5/3-D24-ICOSL-CD40L, an oncolytic vector, with an anti-PD-1 monoclonal antibody.

Methods: The efficacy of the vector was confirmed in vitro in three mesothelioma cell lines - H226, Mero-82, and MSTO-211H, and subsequently the antineoplastic properties in combination with anti-PD-1 was evaluated in xenograft H226 mesothelioma BALB/c and humanized NSG mouse models.

Results and discussion: Anticancer efficacy was attributed to reduced tumour volume and increased infiltration of tumour infiltrating lymphocytes, including activated cytotoxic T-cells (GrB+CD8+). Additionally, a correlation between tumour volume and activated CD8+ tumour infiltrating lymphocytes was observed. These findings were confirmed by transcriptomic analysis carried out on resected human tumour tissue, which also revealed upregulation of CD83 and CRTAM, as well as several chemokines (CXCL3, CXCL9, CXCL11) in the tumour microenvironment. Furthermore, according to observations, the combinatorial therapy had the strongest effect on reducing mesothelin and MUC16 levels. Gene set enrichment analysis suggested that the combinatorial therapy induced changes to the expression of genes belonging to the "adaptive immune response" gene ontology category. Combinatorial therapy with oncolytic adenovirus with checkpoint inhibitors may improve anticancer efficacy and survival by targeted cancer cell destruction and triggering of immunogenic cell death. Obtained results support further assessment of the AdV5/3-D24-ICOSL-CD40L in combination with checkpoint inhibitors as a novel therapeutic perspective for mesothelioma treatment.

Keywords: CD40L; ICOSL; TILs; anti PD-1; immune checkpoint inhibitors; immunotherapy; mesothelioma; oncolytic adenovirus.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. LK was supported by the National Science Centre, Poland, SONATA (2022/47/D/NZ7/03212), SONATINA (2019/32/C/NZ7/00156), and the National Institute of Public Health NIH – National Research Institute, Poland (BW-3/2023, 1BWBW/2022). M.G. acknowledges STARS Starting Grant (STARS StG) (Grant Number: GARO_STARS_MUR22_01) funded by the University of Padua. This publication is based on work in COST Action CA 17140 “Cancer Nanomedicine from the Bench to the Bedside” supported by COST (European Cooperation in Science and Technology) (LK, MG). MS was supported by the Centre for Advanced Materials and Technologies, WUT, Poland and grant POB BioTechMed-1 No. 504/04496/1020/45.010406 and BIOTECHMED-LAB-1 (Excellence Initiative Research University). ML was partially supported by IDUB against COVID-19 project granted by Warsaw University of Technology under the Excellence Initiative Program: Research University (IDUB). DP research was funded by Warsaw University of Technology under the Excellence Initiative Program: Research University (IDUB) and co-supported by Polish National Science Centre (2019/35/O/ST6/02484 and 2020/37/B/NZ2/03757). Computations were performed using the Artificial Intelligence HPC platform financed by the Polish Ministry of Science and Higher Education (Decision No. 7054/IA/SP/2020 of 2020-08-28). TS research was co-funded by (POB Biotechnology and Biomedical Engineering) of Warsaw University of Technology within the Excellence Initiative Program: Research University (IDUB).