Neoadjuvant PD-1 Blockade in Glioblastoma
Evaluation of changes in the tumour immune microenvironment
Two letters published on 11 February 2019 in the Nature Medicine reveal feasibility, safety and immunobiological effects of neoadjuvant PD-1 blockade in patients with glioblastoma, while the third letter provides perspective on immune and genomic correlates of response to anti-PD-1 therapy in glioblastoma.
In first letter Ignacio Melero of the Centro de Investigación Biomedica en Red de Oncología, Madrid, Instituto de Investigación Sanitaria de Navarra, Pamplona, and Clínica Universidad de Navarra, Pamplona, Spain and co-authors reported the results of neoadjuvant PD-1 blockade in patients undergoing surgery for glioblastoma from a single-arm phase II clinical trial. In the study, they tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients. In these patients, 27 salvage surgeries were performed for recurrent cases and primary surgery for newly diagnosed patients in 3 cases.
Availability of tumour tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumour 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 tumour 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.
In the second letter Timothy F. Cloughesy and Robert M. Prins of the David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA reported the results from a randomised, multi-institution clinical trial conducted by The Ivy Foundation Early Phase Clinical Trials Consortium in order to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma.
Patients who were randomised to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomised to receive adjuvant, post-surgical PD-1 blockade alone.
Neoadjuvant PD-1 blockade was associated with upregulation of T cell– and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumour, which was not seen in patients that received adjuvant therapy alone. Focal induction of PD-L1 in the tumour microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting.
The authors concluded that the findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response.
In third letter, Fabio M. Iwamoto of the Columbia University Irving Medical Center, New York, Adam M. Sonabend of the Northwestern University Feinberg School of Medicine, Chicago, and Raul Rabadan of the Columbia University, New York, USA and colleagues report molecular determinants of immunotherapeutic response in glioblastoma. They longitudinally profiled 66 patients, including 17 long-term responders, during standard therapy and after treatment with PD-1 inhibitors, nivolumab or pembrolizumab.
Genomic and transcriptomic analysis revealed a significant enrichment of PTEN mutations associated with immunosuppressive expression signatures in non-responders, and an enrichment of PTPN11 and BRAF that are MAPK pathway alterations in responders.
Responsive tumours were also associated with branched patterns of evolution from the elimination of neoepitopes as well as with differences in T cell clonal diversity and tumour microenvironment profiles.
The authors concluded that clinical response to anti-PD-1 immunotherapy in glioblastoma is associated with specific molecular alterations, immune expression signatures, and immune infiltration that reflect the tumour clonal evolution during treatment.
The European Medicines Agency has released two bioequivalence guidance for public consultation: