TY - JOUR
T1 - T Cell-Activating Mesenchymal Stem Cells as a Biotherapeutic for HCC
AU - Szoor, Arpad
AU - Vaidya, Abishek
AU - Velasquez, Mireya Paulina
AU - Mei, Zhuyong
AU - Galvan, Daniel L.
AU - Torres, David
AU - Gee, Adrian
AU - Heczey, Andras
AU - Gottschalk, Stephen
N1 - Funding Information:
The authors would like to thank Dr. Malcolm Brenner (Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX) for helpful discussions and advice. This work was supported by NIH grants P01CA094237 and 2 P30 CA125123-09 . A.S. was supported by the Hungarian Talent Program ( NTP-NFTÖ-16-0912 ).
Publisher Copyright:
© 2017 The Authors
PY - 2017/9/15
Y1 - 2017/9/15
N2 - The outcome for advanced stage hepatocellular carcinoma (HCC) remains poor, highlighting the need for novel therapies. Genetically modified mesenchymal stem cells (MSCs) are actively being explored as cancer therapeutics due to their inherent ability to migrate to tumor sites. We reasoned that MSCs can be genetically modified to redirect T cells to Glypican-3 (GPC3)+ HCC, and genetically modified these with viral vectors encoding a GPC3/CD3 bispecific T cell engager (GPC3-ENG), a bispecifc T cell engager specific for an irrelevant antigen (EGFRvIII), and/or costimulatory molecules (CD80 and 41BBL). Coculture of GPC3+ cells, GPC3-ENG MSCs, and T cells resulted in T cell activation, as judged by interferon γ (IFNγ) production and killing of tumor cells by T cells. Modification of GPC3-ENG MSCs with CD80 and 41BBL was required for antigen-dependent interleukin-2 (IL-2) production by T cells and resulted in faster tumor cell killing by redirected T cells. In vivo, GPC3-ENG MSCs ± costimulatory molecules had antitumor activity in the HUH7 HCC xenograft model, resulting in a survival advantage. In conclusion, MSCs genetically modified to express GPC3-ENG ± costimulatory molecules redirect T cells to GPC3+ tumor cells and have potent antitumor activity. Thus, further preclinical exploration of our modified approach to GPC3-targeted immunotherapy for HCC is warranted.
AB - The outcome for advanced stage hepatocellular carcinoma (HCC) remains poor, highlighting the need for novel therapies. Genetically modified mesenchymal stem cells (MSCs) are actively being explored as cancer therapeutics due to their inherent ability to migrate to tumor sites. We reasoned that MSCs can be genetically modified to redirect T cells to Glypican-3 (GPC3)+ HCC, and genetically modified these with viral vectors encoding a GPC3/CD3 bispecific T cell engager (GPC3-ENG), a bispecifc T cell engager specific for an irrelevant antigen (EGFRvIII), and/or costimulatory molecules (CD80 and 41BBL). Coculture of GPC3+ cells, GPC3-ENG MSCs, and T cells resulted in T cell activation, as judged by interferon γ (IFNγ) production and killing of tumor cells by T cells. Modification of GPC3-ENG MSCs with CD80 and 41BBL was required for antigen-dependent interleukin-2 (IL-2) production by T cells and resulted in faster tumor cell killing by redirected T cells. In vivo, GPC3-ENG MSCs ± costimulatory molecules had antitumor activity in the HUH7 HCC xenograft model, resulting in a survival advantage. In conclusion, MSCs genetically modified to express GPC3-ENG ± costimulatory molecules redirect T cells to GPC3+ tumor cells and have potent antitumor activity. Thus, further preclinical exploration of our modified approach to GPC3-targeted immunotherapy for HCC is warranted.
KW - GPC3
KW - bispecific antibody
KW - hepatocellular carcinoma
KW - immunotherapy
UR - http://www.scopus.com/inward/record.url?scp=85029289824&partnerID=8YFLogxK
U2 - 10.1016/j.omto.2017.07.002
DO - 10.1016/j.omto.2017.07.002
M3 - Article
AN - SCOPUS:85029289824
VL - 6
SP - 69
EP - 79
JO - Molecular Therapy - Oncolytics
JF - Molecular Therapy - Oncolytics
SN - 2372-7705
ER -