TY - JOUR
T1 - Adenovirus Armed With TNFa and IL2 Added to aPD-1 Regimen Mediates Antitumor Efficacy in Tumors Refractory to aPD-1
AU - Cervera-Carrascon, Victor
AU - Quixabeira, Dafne C. A.
AU - Santos, Joao M.
AU - Havunen, Riikka
AU - Milenova, Ioanna
AU - Verhoeff, Jan
AU - Heiniö, Camilla
AU - Zafar, Sadia
AU - Garcia-Vallejo, Juan J.
AU - van Beusechem, Victor W.
AU - de Gruijl, Tanja D.
AU - Kalervo, Aino
AU - Sorsa, Suvi
AU - Kanerva, Anna
AU - Hemminki, Akseli
N1 - Funding Information: This study was supported by Marie Skłodowska-Curie Innovative Training Networks (ITN-EID VIRION H2020-MSCA-ITN-2014 project number 643130), Orion Research Foundation, Jane and Aatos Erkko Foundation, HUCH Research Funds (VTR), Sigrid Juselius Foundation, Finnish Cancer Organizations, University of Helsinki, TILT Biotherapeutics Ltd, Novo Nordisk Foundation, Päivikki and Sakari Sohlberg Foundation and the Finnish Society of Sciences And Letters. TILT Biotherapeutics Ltd was not involved in study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. We also thank Albert Ehrnrooth and Karl Fazer for research support. Funding Information: We take the opportunity to thank Susanna Gr?nberg-V?h?-Koskela, Riikka Kalliokoski and Minna Oksanen for their valuable support across the study. The Laboratory Animal Centre (University of Helsinki) is highly appreciated for their technical support. Publisher Copyright: © Copyright © 2021 Cervera-Carrascon, Quixabeira, Santos, Havunen, Milenova, Verhoeff, Heiniö, Zafar, Garcia-Vallejo, van Beusechem, de Gruijl, Kalervo, Sorsa, Kanerva and Hemminki. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/7/23
Y1 - 2021/7/23
N2 - Immune checkpoint inhibitors such as anti-PD-1 have revolutionized the field of oncology over the past decade. Nevertheless, the majority of patients do not benefit from them. Virotherapy is a flexible tool that can be used to stimulate and/or recruit different immune populations. T-cell enabling virotherapy could enhance the efficacy of immune checkpoint inhibitors, even in tumors resistant to these inhibitors. The T-cell potentiating virotherapy used here consisted of adenoviruses engineered to express tumor necrosis factor alpha and interleukin-2 in the tumor microenvironment. To study virus efficacy in checkpoint-inhibitor resistant tumors, we developed an anti-PD-1 resistant melanoma model in vivo. In resistant tumors, adding virotherapy to an anti-PD-1 regimen resulted in increased survival (p=0.0009), when compared to anti-PD-1 monotherapy. Some of the animals receiving virotherapy displayed complete responses, which did not occur in the immune checkpoint-inhibitor monotherapy group. When adenoviruses were delivered into resistant tumors, there were signs of increased CD8 T-cell infiltration and activation, which - together with a reduced presence of M2 macrophages and myeloid-derived suppressor cells - could explain those results. T-cell enabling virotherapy appeared as a valuable tool to counter resistance to immune checkpoint inhibitors. The clinical translation of this approach could increase the number of cancer patients benefiting from immunotherapies.
AB - Immune checkpoint inhibitors such as anti-PD-1 have revolutionized the field of oncology over the past decade. Nevertheless, the majority of patients do not benefit from them. Virotherapy is a flexible tool that can be used to stimulate and/or recruit different immune populations. T-cell enabling virotherapy could enhance the efficacy of immune checkpoint inhibitors, even in tumors resistant to these inhibitors. The T-cell potentiating virotherapy used here consisted of adenoviruses engineered to express tumor necrosis factor alpha and interleukin-2 in the tumor microenvironment. To study virus efficacy in checkpoint-inhibitor resistant tumors, we developed an anti-PD-1 resistant melanoma model in vivo. In resistant tumors, adding virotherapy to an anti-PD-1 regimen resulted in increased survival (p=0.0009), when compared to anti-PD-1 monotherapy. Some of the animals receiving virotherapy displayed complete responses, which did not occur in the immune checkpoint-inhibitor monotherapy group. When adenoviruses were delivered into resistant tumors, there were signs of increased CD8 T-cell infiltration and activation, which - together with a reduced presence of M2 macrophages and myeloid-derived suppressor cells - could explain those results. T-cell enabling virotherapy appeared as a valuable tool to counter resistance to immune checkpoint inhibitors. The clinical translation of this approach could increase the number of cancer patients benefiting from immunotherapies.
KW - adenovirus
KW - cancer immunotherapy
KW - checkpoint inhibitor resistance
KW - oncolytic virus
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85112486012&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fimmu.2021.706517
DO - https://doi.org/10.3389/fimmu.2021.706517
M3 - Article
C2 - 34367166
SN - 1664-3224
VL - 12
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 706517
ER -