TY - JOUR
T1 - Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma
AU - Schalper, Kurt A.
AU - Rodriguez-Ruiz, Maria E.
AU - Diez-Valle, Ricardo
AU - López-Janeiro, Alvaro
AU - Porciuncula, Angelo
AU - Idoate, Miguel A.
AU - Inogés, Susana
AU - de Andrea, Carlos
AU - López-Diaz de Cerio, Ascensión
AU - Tejada, Sonia
AU - Berraondo, Pedro
AU - Villarroel-Espindola, Franz
AU - Choi, Jungmin
AU - Gúrpide, Alfonso
AU - Giraldez, Miriam
AU - Goicoechea, Iosune
AU - Gallego Perez-Larraya, Jaime
AU - Sanmamed, Miguel F.
AU - Perez-Gracia, Jose L.
AU - Melero, Ignacio
N1 - Funding Information:
We thank R. Latek and D. McDonald from Bristol-Myers Squibb and the study coordinators and staff from our Clinical Research Unit, E. Guirado, L. Resano and B. Palencia for project coordination. We also thank Laura Johnson and Josh Haimes from ArcherDx for experimental and technical support. Financial support was through the Immunoncology Network (I-ON) supported by Bristol-Myers Squibb. Additional funds came to K.A.S. from Department of Defense LCRP Career Development Award W81XWH-16-1-0160, NIH Lung SPORE in Lung Cancer P50CA196530, and Stand Up To Cancer Translational Research Grants SU2C-AACR-DT17-15 and SU2C-AACR-DT22-17, and to I.M. from MINECO (SAF2014-52361-R and 2017-83267-C2-1-R), Fundación de la Asociación Española Contra el Cáncer (AECC), Fundación BBVA. M.E.R.-R. received a Rio Hortega contract from ISCIII.
Funding Information:
K.A.S. is a consultant for Celgene, Moderna Therapeutics and Shattuck Labs and has received research funding from Vasculox, Moderna, Takeda, Surface Oncology, Tesaro, Pierre-Fabre, Merck and Bristol-Myers Squibb. I.M. is a consultant for BMS, Merck-Serono, Roche-Genetech, Tusk, Alligator, Genmab, Molecular Partners, F-Star, Bayer, Seattle Genetics and Alligator and has received research funding from BMS, Roche, Bioncotech and Alligator. J.L.P.-G. is a consultant for and has received research support, travel grants and lecture fees from BMS and Roche as well as research support and travel grants from MSD.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, produces only modest benefits to survival1,2. Here, to explore the feasibility, safety and immunobiological effects of PD-1 blockade in patients undergoing surgery for glioblastoma, we conducted a single-arm phase II clinical trial (NCT02550249) in which we tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients (27 salvage surgeries for recurrent cases and 3 cases of primary surgery for newly diagnosed patients). Availability of tumor tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumor immune microenvironment using multiple molecular and cellular analyses. Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later.
AB - Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, produces only modest benefits to survival1,2. Here, to explore the feasibility, safety and immunobiological effects of PD-1 blockade in patients undergoing surgery for glioblastoma, we conducted a single-arm phase II clinical trial (NCT02550249) in which we tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients (27 salvage surgeries for recurrent cases and 3 cases of primary surgery for newly diagnosed patients). Availability of tumor tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumor immune microenvironment using multiple molecular and cellular analyses. Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later.
UR - http://www.scopus.com/inward/record.url?scp=85061387091&partnerID=8YFLogxK
U2 - 10.1038/s41591-018-0339-5
DO - 10.1038/s41591-018-0339-5
M3 - Article
C2 - 30742120
AN - SCOPUS:85061387091
SN - 1078-8956
VL - 25
SP - 470
EP - 476
JO - Nature Medicine
JF - Nature Medicine
IS - 3
ER -