Neoadjuvant anti-PD1 immunotherapy for surgically accessible recurrent glioblastoma: clinical and molecular outcomes of a stage 2 single-arm expansion cohort
Abstract Glioblastoma is immunologically “cold” and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrol...
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2024-12-01
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| Online Access: | https://doi.org/10.1038/s41467-024-54326-7 |
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| author | J. Ricardo McFaline-Figueroa Lu Sun Gilbert C. Youssef Raymond Huang Gang Li Jiyoon Kim Eudocia Q. Lee Lakshmi Nayak Ugonma Chukwueke Rameen Beroukhim Tracy T. Batchelor E. Antonio Chiocca Richard G. Everson Lisa Doherty Jennifer Stefanik Kathryn Partridge Amanda Spearman Alexa Myers Catharina Westergaard Alyssa Russ Maria Lavallee Anna Smokovich Corey LaForest-Roys Rachel Garcia Fox Christine McCluskey Wenya Linda Bi Omar Arnaout PierPaolo Peruzzi G. Rees Cosgrove Keith L. Ligon Isabel Arrillaga-Romany Jennifer L. Clarke David A. Reardon Timothy F. Cloughesy Robert M. Prins Patrick Y. Wen |
| author_facet | J. Ricardo McFaline-Figueroa Lu Sun Gilbert C. Youssef Raymond Huang Gang Li Jiyoon Kim Eudocia Q. Lee Lakshmi Nayak Ugonma Chukwueke Rameen Beroukhim Tracy T. Batchelor E. Antonio Chiocca Richard G. Everson Lisa Doherty Jennifer Stefanik Kathryn Partridge Amanda Spearman Alexa Myers Catharina Westergaard Alyssa Russ Maria Lavallee Anna Smokovich Corey LaForest-Roys Rachel Garcia Fox Christine McCluskey Wenya Linda Bi Omar Arnaout PierPaolo Peruzzi G. Rees Cosgrove Keith L. Ligon Isabel Arrillaga-Romany Jennifer L. Clarke David A. Reardon Timothy F. Cloughesy Robert M. Prins Patrick Y. Wen |
| author_sort | J. Ricardo McFaline-Figueroa |
| collection | DOAJ |
| description | Abstract Glioblastoma is immunologically “cold” and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we enrolled an additional 25 patients with a primary endpoint of evaluating the cell cycle gene signature associated with neoadjuvant pembrolizumab and performed bulk-RNA seq on resected tumor tissue (NCT02852655). Neoadjuvant pembrolizumab was associated with suppression of cell cycle/cancer proliferation genes and upregulation of T-cell/interferon-related gene expression. This signature was unique to patients treated with neoadjuvant pembrolizumab and was an independent positive risk factor for survival. Our results demonstrate a clear pharmacodynamic effect of anti-PD1 therapy in glioblastoma and identify pathways that may mediate resistance. However, we did not confirm a survival benefit to neoadjuvant pembrolizumab in recurrent glioblastoma and our secondary endpoint of PFS-6 was 19.5% (95% CI: 9.29-41.2%) for the pooled neoadjuvant cohorts. Our new data suggests some patients may exhibit innate resistance to pre-surgical ICI and require other concomitant therapies to sensitize effectively. |
| format | Article |
| id | doaj-art-2a14eb41232745739d6825fdc4fd6b38 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-2a14eb41232745739d6825fdc4fd6b382025-01-05T12:35:13ZengNature PortfolioNature Communications2041-17232024-12-011511910.1038/s41467-024-54326-7Neoadjuvant anti-PD1 immunotherapy for surgically accessible recurrent glioblastoma: clinical and molecular outcomes of a stage 2 single-arm expansion cohortJ. Ricardo McFaline-Figueroa0Lu Sun1Gilbert C. Youssef2Raymond Huang3Gang Li4Jiyoon Kim5Eudocia Q. Lee6Lakshmi Nayak7Ugonma Chukwueke8Rameen Beroukhim9Tracy T. Batchelor10E. Antonio Chiocca11Richard G. Everson12Lisa Doherty13Jennifer Stefanik14Kathryn Partridge15Amanda Spearman16Alexa Myers17Catharina Westergaard18Alyssa Russ19Maria Lavallee20Anna Smokovich21Corey LaForest-Roys22Rachel Garcia Fox23Christine McCluskey24Wenya Linda Bi25Omar Arnaout26PierPaolo Peruzzi27G. Rees Cosgrove28Keith L. Ligon29Isabel Arrillaga-Romany30Jennifer L. Clarke31David A. Reardon32Timothy F. Cloughesy33Robert M. Prins34Patrick Y. Wen35Center for Neuro-Oncology, Dana-Farber Cancer InstituteDepartment of Neurosurgery, University of California Los AngelesCenter for Neuro-Oncology, Dana-Farber Cancer InstituteDepartment of Radiology, Brigham and Women’s Hospital, Harvard Medical SchoolDepartment of Biostatistics, Jonathan and Karin Fielding School of Public Health, University of California Los AngelesDepartment of Biostatistics, Jonathan and Karin Fielding School of Public Health, University of California Los AngelesCenter for Neuro-Oncology, Dana-Farber Cancer InstituteCenter for Neuro-Oncology, Dana-Farber Cancer InstituteCenter for Neuro-Oncology, Dana-Farber Cancer InstituteCenter for Neuro-Oncology, Dana-Farber Cancer InstituteCenter for Neuro-Oncology, Dana-Farber Cancer InstituteDepartment of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical SchoolDepartment of Neurosurgery, University of California Los AngelesCenter for Neuro-Oncology, Dana-Farber Cancer InstituteCenter for Neuro-Oncology, Dana-Farber Cancer InstituteCenter for Neuro-Oncology, Dana-Farber Cancer InstituteCenter for Neuro-Oncology, Dana-Farber Cancer InstituteCenter for Neuro-Oncology, Dana-Farber Cancer InstituteCenter for Neuro-Oncology, Dana-Farber Cancer InstituteCenter for Neuro-Oncology, Dana-Farber Cancer InstituteCenter for Neuro-Oncology, Dana-Farber Cancer InstituteCenter for Neuro-Oncology, Dana-Farber Cancer InstituteCenter for Neuro-Oncology, Dana-Farber Cancer InstituteCenter for Neuro-Oncology, Dana-Farber Cancer InstituteCenter for Neuro-Oncology, Dana-Farber Cancer InstituteDepartment of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical SchoolDepartment of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical SchoolDepartment of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical SchoolDepartment of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical SchoolDivision of Neuropathology, Brigham and Women’s Hospital, Harvard Medical SchoolDivision of Neuro-Oncology, Mass General Cancer Center, Harvard Medical SchoolDepartments of Neurology and Neurological Surgery, University of California San FranciscoCenter for Neuro-Oncology, Dana-Farber Cancer InstituteJonsson Comprehensive Cancer Center, University of California Los AngelesDepartment of Neurosurgery, University of California Los AngelesCenter for Neuro-Oncology, Dana-Farber Cancer InstituteAbstract Glioblastoma is immunologically “cold” and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we enrolled an additional 25 patients with a primary endpoint of evaluating the cell cycle gene signature associated with neoadjuvant pembrolizumab and performed bulk-RNA seq on resected tumor tissue (NCT02852655). Neoadjuvant pembrolizumab was associated with suppression of cell cycle/cancer proliferation genes and upregulation of T-cell/interferon-related gene expression. This signature was unique to patients treated with neoadjuvant pembrolizumab and was an independent positive risk factor for survival. Our results demonstrate a clear pharmacodynamic effect of anti-PD1 therapy in glioblastoma and identify pathways that may mediate resistance. However, we did not confirm a survival benefit to neoadjuvant pembrolizumab in recurrent glioblastoma and our secondary endpoint of PFS-6 was 19.5% (95% CI: 9.29-41.2%) for the pooled neoadjuvant cohorts. Our new data suggests some patients may exhibit innate resistance to pre-surgical ICI and require other concomitant therapies to sensitize effectively.https://doi.org/10.1038/s41467-024-54326-7 |
| spellingShingle | J. Ricardo McFaline-Figueroa Lu Sun Gilbert C. Youssef Raymond Huang Gang Li Jiyoon Kim Eudocia Q. Lee Lakshmi Nayak Ugonma Chukwueke Rameen Beroukhim Tracy T. Batchelor E. Antonio Chiocca Richard G. Everson Lisa Doherty Jennifer Stefanik Kathryn Partridge Amanda Spearman Alexa Myers Catharina Westergaard Alyssa Russ Maria Lavallee Anna Smokovich Corey LaForest-Roys Rachel Garcia Fox Christine McCluskey Wenya Linda Bi Omar Arnaout PierPaolo Peruzzi G. Rees Cosgrove Keith L. Ligon Isabel Arrillaga-Romany Jennifer L. Clarke David A. Reardon Timothy F. Cloughesy Robert M. Prins Patrick Y. Wen Neoadjuvant anti-PD1 immunotherapy for surgically accessible recurrent glioblastoma: clinical and molecular outcomes of a stage 2 single-arm expansion cohort Nature Communications |
| title | Neoadjuvant anti-PD1 immunotherapy for surgically accessible recurrent glioblastoma: clinical and molecular outcomes of a stage 2 single-arm expansion cohort |
| title_full | Neoadjuvant anti-PD1 immunotherapy for surgically accessible recurrent glioblastoma: clinical and molecular outcomes of a stage 2 single-arm expansion cohort |
| title_fullStr | Neoadjuvant anti-PD1 immunotherapy for surgically accessible recurrent glioblastoma: clinical and molecular outcomes of a stage 2 single-arm expansion cohort |
| title_full_unstemmed | Neoadjuvant anti-PD1 immunotherapy for surgically accessible recurrent glioblastoma: clinical and molecular outcomes of a stage 2 single-arm expansion cohort |
| title_short | Neoadjuvant anti-PD1 immunotherapy for surgically accessible recurrent glioblastoma: clinical and molecular outcomes of a stage 2 single-arm expansion cohort |
| title_sort | neoadjuvant anti pd1 immunotherapy for surgically accessible recurrent glioblastoma clinical and molecular outcomes of a stage 2 single arm expansion cohort |
| url | https://doi.org/10.1038/s41467-024-54326-7 |
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