Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma
Alexandra Gyurdieva, Stefan Zajic, Ya-Fang Chang, E Andres Houseman, Shan Zhong, Jaegil Kim, Michael Nathenson, Thomas Faitg, Mary Woessner, David C Turner, Aisha N Hasan, John Glod, Rosandra N Kaplan, Sandra P D'Angelo, Dejka M Araujo, Warren A Chow, Mihaela Druta, George D Demetri, Brian A Van Tine, Stephan A Grupp, Gregg D Fine, Ioanna Eleftheriadou, Alexandra Gyurdieva, Stefan Zajic, Ya-Fang Chang, E Andres Houseman, Shan Zhong, Jaegil Kim, Michael Nathenson, Thomas Faitg, Mary Woessner, David C Turner, Aisha N Hasan, John Glod, Rosandra N Kaplan, Sandra P D'Angelo, Dejka M Araujo, Warren A Chow, Mihaela Druta, George D Demetri, Brian A Van Tine, Stephan A Grupp, Gregg D Fine, Ioanna Eleftheriadou
Abstract
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.
Conflict of interest statement
A.G. is an employee of and holds stocks/shares in GSK and holds stocks/shares in Amgen. St.Z., E.A.H., J.K., M.N., T.F., M.W., D.C.T. and I.E. are employees of and hold stocks/shares in GSK. Y.F.C. is an employee of GSK. Sh.Z. is a former employee of and holds stocks/shares in GS.K. A.N.H. is a former employee of and holds stocks/shares in GSK and receives patents and royalties from Atara Biotherapeutics. J.G. is protocol investigator for SARC and PBTC sponsored studies. R.N.K. and D.M.A. have no disclosures. S.P.D.A. participated on advisory boards for GSK, Nektar, Adaptimmune, and Merck; reports consulting fees from EMD Serono, Amgen, Nektar, Immune design, GSK, Incyte, Merck, Adaptimmune, and Immunocore, and received support for travel expense by Adaptimmune, EMD Serono, and Nektar. WAC reports grant and honoraria received from GSK. M.D. has received consulting fees from Adaptimmune and honoraria from Deciphera. GDD reports leadership roles with Blueprint Medicines, Merrimack Pharmaceuticals (ended Oct 2019), and Translate Bio (ended Sept 2021); stocks/options/shares in Blueprint Medicines, G1 Therapeutics, Caris Life Sciences, Erasca Pharmaceuticals, RELAY Therapeutics, Bessor Pharmaceuticals, CellCarta, IKENA Oncology, Kojin Therapeutics, and IDRX; paid consulting fees from Bayer, Pfizer, Novartis, Roche/Genentech, GSK, PharmaMar, Daiichi Sankyo, GSK, EMD-Serono, MEDSCAPE, Mirati, WCG/Arsenal Capital, MJ Hennessey/OncLive, C4 Therapeutics, Synlogic, McCann Health, G1 Therapeutics, Caris Life Sciences, RELAY Therapeutics, CellCarta, IKENA Oncology, Kojin Therapeutics and IDRX; royalties, patents or licenses from Novartis via Dana Farber for “use patent” of imatinib in GIST; and non-financial interests in AACR Science Policy and Government Affairs Committee and Alexandria Real Estate Equities summit conference series. BAVT received consulting fees from ADRx, Ayala Pharmaceuticals, Cytokinetics Inc, and Bayer; has honoraria from Adaptimmune Ltd, GSK, Bionest Partiners, and Intellisphere LLC; has received payment for expert testimony from Hinshaw & Culbertson LLP, Rodney Law, CRICO Risk Management Foundation, and Tracey & Fox Law Firm; has received research funding from GSK, Merck, Pfizer, and Tracon; has received travel, accommodations, and expenses from GSK and Adaptimmune; has participated on advisory board meeting with Adaptimmune Ltd, Apexigen Inc, Boehringer Ingelheim, Daiichi Sankyo, Deciphera Pharmaceuticals Inc, Epizyme, GSK, Novartis, PTC Therapeutics, and Lilly, and is a board member for Polaris; and holds royalties or licenses for work performed with Accuronix Therapeutics. S.A.G. has received grants for study support from Novartis, Jazz Pharmaceuticals, Kite, Vertex, and Servier; has received consulting fees from Novartis, Roche, GSK, Vertex/CRISPR, CBMG, and Janssen/JnJ; has received payment for expert testimony from Irwin Mitchell and Jones Day; has patents managed according to the University of Pennsylvania patent policy; has participated on advisory boards for Novartis, Jazz Pharmaceuticals, Adaptimmune, Cellectis, Juno, Vertex, Allogene, and Cabaletta. G.D.F. is a former employee of GSK and has stock options in GSK and PACT Pharma, and holds stocks in Bluebird Bio, Agios, and BioMarin.
© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
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