TY - JOUR
T1 - Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma
AU - Gyurdieva, Alexandra
AU - Zajic, Stefan
AU - Chang, Ya Fang
AU - Houseman, E. Andres
AU - Zhong, Shan
AU - Kim, Jaegil
AU - Nathenson, Michael
AU - Faitg, Thomas
AU - Woessner, Mary
AU - Turner, David C.
AU - Hasan, Aisha N.
AU - Glod, John
AU - Kaplan, Rosandra N.
AU - D’Angelo, Sandra P.
AU - Araujo, Dejka M.
AU - Chow, Warren A.
AU - Druta, Mihaela
AU - Demetri, George D.
AU - Van Tine, Brian A.
AU - Grupp, Stephan A.
AU - Fine, Gregg D.
AU - Eleftheriadou, Ioanna
N1 - Funding Information:
We thank the patients, their families, and site coordinators and staff for their involvement in this study. Study funded by GlaxoSmithKline (208466). We thank Aiman Shalabi, Laura Pearce, Laura Johnson, Jenna Tress, Tim Young, Julie Edwards, Joseph Harding, Shreyan Banerjee, Kishan Dhusia, Uma Saxena, Yash Gandhi, Meenakshi Srinivasan, Tom McKevitt, and Martijn Brugman for their valuable contributions and feedback. Editorial support was provided by Frankie Wignall, PhD, of Fishawack Indicia Ltd, UK, and was funded by GlaxoSmithKline.
Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2022/12
Y1 - 2022/12
N2 - Autologous T cells transduced to express a high affinity T-cell receptor specific to NY-ESO-1 (letetresgene autoleucel, lete-cel) show promise in the treatment of metastatic synovial sarcoma, with 50% overall response rate. The efficacy of lete-cel treatment in 45 synovial sarcoma patients (NCT01343043) has been previously reported, however, biomarkers predictive of response and resistance remain to be better defined. This post-hoc analysis identifies associations of response to lete-cel with lymphodepleting chemotherapy regimen (LDR), product attributes, cell expansion, cytokines, and tumor gene expression. Responders have higher IL-15 levels pre-infusion (p = 0.011) and receive a higher number of transduced effector memory (CD45RA- CCR7-) CD8 + cells per kg (p = 0.039). Post-infusion, responders have increased IFNγ, IL-6, and peak cell expansion (p < 0.01, p < 0.01, and p = 0.016, respectively). Analysis of tumor samples post-treatment illustrates lete-cel infiltration and a decrease in expression of macrophage genes, suggesting remodeling of the tumor microenvironment. Here we report potential predictive and pharmacodynamic markers of lete-cel response that may inform LDR, cell dose, and strategies to enhance anticancer efficacy.
AB - Autologous T cells transduced to express a high affinity T-cell receptor specific to NY-ESO-1 (letetresgene autoleucel, lete-cel) show promise in the treatment of metastatic synovial sarcoma, with 50% overall response rate. The efficacy of lete-cel treatment in 45 synovial sarcoma patients (NCT01343043) has been previously reported, however, biomarkers predictive of response and resistance remain to be better defined. This post-hoc analysis identifies associations of response to lete-cel with lymphodepleting chemotherapy regimen (LDR), product attributes, cell expansion, cytokines, and tumor gene expression. Responders have higher IL-15 levels pre-infusion (p = 0.011) and receive a higher number of transduced effector memory (CD45RA- CCR7-) CD8 + cells per kg (p = 0.039). Post-infusion, responders have increased IFNγ, IL-6, and peak cell expansion (p < 0.01, p < 0.01, and p = 0.016, respectively). Analysis of tumor samples post-treatment illustrates lete-cel infiltration and a decrease in expression of macrophage genes, suggesting remodeling of the tumor microenvironment. Here we report potential predictive and pharmacodynamic markers of lete-cel response that may inform LDR, cell dose, and strategies to enhance anticancer efficacy.
UR - http://www.scopus.com/inward/record.url?scp=85137570700&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-32491-x
DO - 10.1038/s41467-022-32491-x
M3 - Article
C2 - 36075914
AN - SCOPUS:85137570700
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 5296
ER -