TY - JOUR
T1 - PD1 Blockade Enhances ICAM1-Directed CAR T Therapeutic Efficacy in Advanced Thyroid Cancer
AU - Gray, Katherine D.
AU - McCloskey, Jaclyn E.
AU - Vedvyas, Yogindra
AU - Kalloo, Olivia R.
AU - Eshaky, Steve El
AU - Yang, Yanping
AU - Shevlin, Enda
AU - Zaman, Marjan
AU - Ullmann, Timothy M.
AU - Liang, Heng
AU - Stefanova, Dessislava
AU - Christos, Paul J.
AU - Scognamiglio, Theresa
AU - Tassler, Andrew B.
AU - Zarnegar, Rasa
AU - Fahey, Thomas J.
AU - Jin, Moonsoo M.
AU - Min, Irene M.
N1 - Funding Information:
This working is supported by the Bite Me Cancer–American Thyroid Association (ID-2016-052; to I.M. Min), New York State Department of Health (DOH-01-C32575GG-34500; to I.M. Min), Emerson Collective Cancer Research Fund (ECCRF 191824-01; to I.M. Min), NCI R01 CA217059 (to M.M. Jin), and Dancer's Care Foundation (to T.J. Fahey). The authors would like to acknowledge the support of the Translational Research, Clinical & Translational Science Center (1-UL1-TR002384-01), Flow cytometry Core, and the CITI Biomedical Imaging Center, all at Weill Cornell Medicine.
Funding Information:
This working is supported by the Bite Me Cancer-American Thyroid Association (ID-2016-052; to I.M. Min), New York State Department of Health (DOH-01C32575GG-34500; to I.M. Min), Emerson Collective Cancer Research Fund (ECCRF 191824-01; to I.M. Min), NCI R01 CA217059 (to M.M. Jin), and Dancer's Care Foundation (to T.J. Fahey). The authors would like to acknowledge the support of the Translational Research, Clinical & Translational Science Center (1-UL1-TR002384-01), Flow cytometry Core, and the CITI Biomedical Imaging Center, all at Weill Cornell Medicine.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/11/15
Y1 - 2020/11/15
N2 - PURPOSE: Advanced thyroid cancers, including poorly differentiated and anaplastic thyroid cancer (ATC), are lethal malignancies with limited treatment options. The majority of patients with ATC have responded poorly to programmed death 1 (PD1) blockade in early clinical trials. There is a need to explore new treatment options.EXPERIMENTAL DESIGN: We examined the expression of PD-L1 (a ligand of PD1) and intercellular adhesion molecule 1 (ICAM1) in thyroid tumors and ATC cell lines, and investigated the PD1 expression level in peripheral T cells of patients with thyroid cancer. Next, we studied the tumor-targeting efficacy and T-cell dynamics of monotherapy and combination treatments of ICAM1-targeting chimeric antigen receptor (CAR) T cells and anti-PD1 antibody in a xenograft model of ATC.RESULTS: Advanced thyroid cancers were associated with increased expression of both ICAM1 and PD-L1 in tumors, and elevated PD1 expression in CD8+ T cells of circulating blood. The expression of ICAM1 and PD-L1 in ATC lines was regulated by the IFNγ-JAK2 signaling pathway. ICAM1-targeted CAR T cells, produced from either healthy donor or patient T cells, in combination with PD1 blockade demonstrated an improved ability to eradicate ICAM1-expressing target tumor cells compared with CAR T treatment alone. PD1 blockade facilitated clearance of PD-L1 high tumor colonies and curtailed excessive CAR T expansion, resulting in rapid tumor clearance and prolonged survival in a mouse model.CONCLUSIONS: Targeting two IFNγ-inducible, tumor-associated antigens-ICAM1 and PD-L1-in a complementary manner might be an effective treatment strategy to control advanced thyroid cancers in vivo.
AB - PURPOSE: Advanced thyroid cancers, including poorly differentiated and anaplastic thyroid cancer (ATC), are lethal malignancies with limited treatment options. The majority of patients with ATC have responded poorly to programmed death 1 (PD1) blockade in early clinical trials. There is a need to explore new treatment options.EXPERIMENTAL DESIGN: We examined the expression of PD-L1 (a ligand of PD1) and intercellular adhesion molecule 1 (ICAM1) in thyroid tumors and ATC cell lines, and investigated the PD1 expression level in peripheral T cells of patients with thyroid cancer. Next, we studied the tumor-targeting efficacy and T-cell dynamics of monotherapy and combination treatments of ICAM1-targeting chimeric antigen receptor (CAR) T cells and anti-PD1 antibody in a xenograft model of ATC.RESULTS: Advanced thyroid cancers were associated with increased expression of both ICAM1 and PD-L1 in tumors, and elevated PD1 expression in CD8+ T cells of circulating blood. The expression of ICAM1 and PD-L1 in ATC lines was regulated by the IFNγ-JAK2 signaling pathway. ICAM1-targeted CAR T cells, produced from either healthy donor or patient T cells, in combination with PD1 blockade demonstrated an improved ability to eradicate ICAM1-expressing target tumor cells compared with CAR T treatment alone. PD1 blockade facilitated clearance of PD-L1 high tumor colonies and curtailed excessive CAR T expansion, resulting in rapid tumor clearance and prolonged survival in a mouse model.CONCLUSIONS: Targeting two IFNγ-inducible, tumor-associated antigens-ICAM1 and PD-L1-in a complementary manner might be an effective treatment strategy to control advanced thyroid cancers in vivo.
KW - Animals
KW - B7-H1 Antigen/antagonists & inhibitors
KW - CD8-Positive T-Lymphocytes/drug effects
KW - Cell Line, Tumor
KW - Gene Expression Regulation, Neoplastic
KW - Heterografts
KW - Humans
KW - Immune Checkpoint Inhibitors/pharmacology
KW - Intercellular Adhesion Molecule-1/genetics
KW - Interferon-gamma/genetics
KW - Janus Kinase 2/genetics
KW - Mice
KW - Neoplasm Staging
KW - Programmed Cell Death 1 Receptor/antagonists & inhibitors
KW - Thyroid Carcinoma, Anaplastic/drug therapy
KW - Thyroid Neoplasms/drug therapy
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U2 - 10.1158/1078-0432.CCR-20-1523
DO - 10.1158/1078-0432.CCR-20-1523
M3 - Article
C2 - 32887724
AN - SCOPUS:85101450312
SN - 1078-0432
VL - 26
SP - 6003
EP - 6016
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -