TY - JOUR
T1 - CD40L coding oncolytic adenovirus allows long-term survival of humanized mice receiving dendritic cell therapy
AU - Zafar, Sadia
AU - Sorsa, Suvi
AU - Siurala, Mikko
AU - Hemminki, Otto
AU - Havunen, Riikka
AU - Cervera-Carrascon, Victor
AU - Santos, João Manuel
AU - Wang, Hongjie
AU - Lieber, Andre
AU - de Gruijl, Tanja
AU - Kanerva, Anna
AU - Hemminki, Akseli
PY - 2018
Y1 - 2018
N2 - Dendritic cells (DCs) are crucial players in promoting immune responses. Logically, adoptive DC therapy is a promising approach in cancer immunotherapy. One of the major obstacles in cancer immunotherapy in general is the immunosuppressive tumor microenvironment, which hampers the maturation and activation of DCs. Therefore, human clinical outcomes with DC therapy alone have been disappointing. In this study, we use fully serotype 3 oncolytic adenovirus Ad3-hTERT-CMV-hCD40L, expressing human CD40L, to modulate the tumor microenvironment with subsequently improved function of DCs. We evaluated the synergistic effects of Ad3-hTERT-CMV-hCD40L and DCs in the presence of human peripheral blood mononuclear cells ex vivo and in vivo. Tumors treated with Ad3-hTERT-CMV-hCD40L and DCs featured greater antitumor effect compared with unarmed virus or either treatment alone. 100% of humanized mice survived to the end of the experiment, while mice in all other groups died by day 88. Moreover, adenovirally-delivered CD40L induced activation of DCs, leading to induction of Th1 immune responses. These results support clinical trials with Ad3-hTERT-CMV-hCD40L in patients receiving DC therapy.
AB - Dendritic cells (DCs) are crucial players in promoting immune responses. Logically, adoptive DC therapy is a promising approach in cancer immunotherapy. One of the major obstacles in cancer immunotherapy in general is the immunosuppressive tumor microenvironment, which hampers the maturation and activation of DCs. Therefore, human clinical outcomes with DC therapy alone have been disappointing. In this study, we use fully serotype 3 oncolytic adenovirus Ad3-hTERT-CMV-hCD40L, expressing human CD40L, to modulate the tumor microenvironment with subsequently improved function of DCs. We evaluated the synergistic effects of Ad3-hTERT-CMV-hCD40L and DCs in the presence of human peripheral blood mononuclear cells ex vivo and in vivo. Tumors treated with Ad3-hTERT-CMV-hCD40L and DCs featured greater antitumor effect compared with unarmed virus or either treatment alone. 100% of humanized mice survived to the end of the experiment, while mice in all other groups died by day 88. Moreover, adenovirally-delivered CD40L induced activation of DCs, leading to induction of Th1 immune responses. These results support clinical trials with Ad3-hTERT-CMV-hCD40L in patients receiving DC therapy.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85052132756&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30386680
U2 - https://doi.org/10.1080/2162402X.2018.1490856
DO - https://doi.org/10.1080/2162402X.2018.1490856
M3 - Article
C2 - 30386680
SN - 2162-4011
VL - 7
JO - OncoImmunology
JF - OncoImmunology
IS - 10
M1 - e1490856
ER -