Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer
Background Sipuleucel-T is a US Food and Drug Administration-approved autologous cellular immunotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We examined whether administering ipilimumab after sipuleucel-T could modify immune and/or clinical...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2021-05-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/9/5/e002254.full |
| _version_ | 1818885510580404224 |
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| author | Padmanee Sharma Sumit Subudhi James P Allison Rahul Aggarwal Eric J Small Terence W Friedlander Brandon Chen Jaqueline Marquez Kate Allaire Alexander Cheung Sharon Ng Christopher Nguyen Matthew Spitzer |
| author_facet | Padmanee Sharma Sumit Subudhi James P Allison Rahul Aggarwal Eric J Small Terence W Friedlander Brandon Chen Jaqueline Marquez Kate Allaire Alexander Cheung Sharon Ng Christopher Nguyen Matthew Spitzer |
| author_sort | Padmanee Sharma |
| collection | DOAJ |
| description | Background Sipuleucel-T is a US Food and Drug Administration-approved autologous cellular immunotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We examined whether administering ipilimumab after sipuleucel-T could modify immune and/or clinical responses to this treatment.Methods A total of 50 patients with mCRPC were enrolled into a clinical trial (NCT01804465, ClinicalTrials.gov) where they received ipilimumab either immediately or delayed 3 weeks following completion of sipuleucel-T treatment. Blood was collected at various timepoints of the study. Luminex assay for anti-prostatic acid phosphatase (PAP) and anti-PA2024-specific serum immunoglobulin G (IgG) and ELISpot for interferon-γ (IFN-γ) production against PAP and PA2024 were used to assess antigen-specific B and T cell responses, respectively. Clinical response was defined as >30% reduction in serum prostate-specific antigen levels compared with pretreatment levels. The frequency and state of circulating immune cells were determined by mass cytometry by time-of-flight and statistical scaffold analysis.Results We found the combination to be well tolerated with no unexpected adverse events occurring. The timing of ipilimumab did not significantly alter the rates of antigen-specific B and T cell responses, the primary endpoint of the clinical trial. Clinical responses were observed in 6 of 50 patients, with 3 having responses lasting longer than 3 months. The timing of ipilimumab did not significantly associate with clinical response or toxicity. The combination treatment did induce CD4 and CD8 T cell activation that was most pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells, even prior to treatment, were associated with better clinical outcomes. Interestingly, these differences in CTLA-4 expression were associated with prior localized radiation therapy (RT) to the prostate or prostatic fossa. Prior radiation treatment was also associated with improved radiographic progression-free survival.Conclusion Combining CTLA-4 blockade with sipuleucel-T resulted in modest clinical activity. The timing of CTLA-4 blockade following sipuleucel-T did not alter antigen-specific responses. Clinical responses were associated with both lower baseline frequencies of CTLA-4 expressing T cells and a history of RT. Prior cancer therapy may therefore result in long-lasting immune changes that influence responsiveness to immunotherapy with sipuleucel-T and anti-CTLA-4. |
| first_indexed | 2024-12-19T16:06:35Z |
| format | Article |
| id | doaj.art-10601fa611a047cb8c2b6cb57d7992a7 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-19T16:06:35Z |
| publishDate | 2021-05-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-10601fa611a047cb8c2b6cb57d7992a72022-12-21T20:14:50ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262021-05-019510.1136/jitc-2020-002254Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancerPadmanee Sharma0Sumit Subudhi1James P Allison2Rahul Aggarwal3Eric J Small4Terence W Friedlander5Brandon Chen6Jaqueline Marquez7Kate Allaire8Alexander Cheung9Sharon Ng10Christopher Nguyen11Matthew Spitzer12Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center Division of Cancer Medicine, Houston, Texas, USADepartment of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center Division of Cancer Medicine, Houston, Texas, USADepartment of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center Division of Cancer Medicine, Houston, Texas, USADepartment Hematology/Oncology, School of Medicine, University of California San Francisco, San Francisco, California, USADepartment Hematology/Oncology, School of Medicine, University of California San Francisco, San Francisco, California, USADepartment Hematology/Oncology, School of Medicine, University of California San Francisco, San Francisco, California, USADepartment Hematology/Oncology, School of Medicine, University of California San Francisco, San Francisco, California, USADepartment Hematology/Oncology, School of Medicine, University of California San Francisco, San Francisco, California, USADepartment Hematology/Oncology, School of Medicine, University of California San Francisco, San Francisco, California, USADepartment Hematology/Oncology, School of Medicine, University of California San Francisco, San Francisco, California, USADepartment Hematology/Oncology, School of Medicine, University of California San Francisco, San Francisco, California, USADepartment Hematology/Oncology, School of Medicine, University of California San Francisco, San Francisco, California, USADepartment of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, California, USABackground Sipuleucel-T is a US Food and Drug Administration-approved autologous cellular immunotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We examined whether administering ipilimumab after sipuleucel-T could modify immune and/or clinical responses to this treatment.Methods A total of 50 patients with mCRPC were enrolled into a clinical trial (NCT01804465, ClinicalTrials.gov) where they received ipilimumab either immediately or delayed 3 weeks following completion of sipuleucel-T treatment. Blood was collected at various timepoints of the study. Luminex assay for anti-prostatic acid phosphatase (PAP) and anti-PA2024-specific serum immunoglobulin G (IgG) and ELISpot for interferon-γ (IFN-γ) production against PAP and PA2024 were used to assess antigen-specific B and T cell responses, respectively. Clinical response was defined as >30% reduction in serum prostate-specific antigen levels compared with pretreatment levels. The frequency and state of circulating immune cells were determined by mass cytometry by time-of-flight and statistical scaffold analysis.Results We found the combination to be well tolerated with no unexpected adverse events occurring. The timing of ipilimumab did not significantly alter the rates of antigen-specific B and T cell responses, the primary endpoint of the clinical trial. Clinical responses were observed in 6 of 50 patients, with 3 having responses lasting longer than 3 months. The timing of ipilimumab did not significantly associate with clinical response or toxicity. The combination treatment did induce CD4 and CD8 T cell activation that was most pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells, even prior to treatment, were associated with better clinical outcomes. Interestingly, these differences in CTLA-4 expression were associated with prior localized radiation therapy (RT) to the prostate or prostatic fossa. Prior radiation treatment was also associated with improved radiographic progression-free survival.Conclusion Combining CTLA-4 blockade with sipuleucel-T resulted in modest clinical activity. The timing of CTLA-4 blockade following sipuleucel-T did not alter antigen-specific responses. Clinical responses were associated with both lower baseline frequencies of CTLA-4 expressing T cells and a history of RT. Prior cancer therapy may therefore result in long-lasting immune changes that influence responsiveness to immunotherapy with sipuleucel-T and anti-CTLA-4.https://jitc.bmj.com/content/9/5/e002254.full |
| spellingShingle | Padmanee Sharma Sumit Subudhi James P Allison Rahul Aggarwal Eric J Small Terence W Friedlander Brandon Chen Jaqueline Marquez Kate Allaire Alexander Cheung Sharon Ng Christopher Nguyen Matthew Spitzer Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer Journal for ImmunoTherapy of Cancer |
| title | Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer |
| title_full | Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer |
| title_fullStr | Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer |
| title_full_unstemmed | Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer |
| title_short | Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer |
| title_sort | pre existing immune status associated with response to combination of sipuleucel t and ipilimumab in patients with metastatic castration resistant prostate cancer |
| url | https://jitc.bmj.com/content/9/5/e002254.full |
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