Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer

• Published in: Journal for immunotherapy of cancer 2021-05, Vol.9 (5), p.e002254
• Main Authors: Sinha, Meenal, Zhang, Li, Subudhi, Sumit, Chen, Brandon, Marquez, Jaqueline, Liu, Eric V, Allaire, Kate, Cheung, Alexander, Ng, Sharon, Nguyen, Christopher, Friedlander, Terence W, Aggarwal, Rahul, Spitzer, Matthew, Allison, James P, Small, Eric J, Sharma, Padmanee, Fong, Lawrence
• Format: Article
• Language: English
• Subjects: Aged; Antibodies; Antigens; Asymptomatic; Biomarkers, Tumor - blood; Cancer therapies; Cancer Vaccines - adverse effects; Cancer Vaccines - therapeutic use; Cells, Cultured; Chemotherapy; Clinical trials; Clinical/Translational Cancer Immunotherapy; CTLA-4 Antigen - antagonists & inhibitors; CTLA-4 Antigen - immunology; Humans; Immune Checkpoint Inhibitors - adverse effects; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy; Ipilimumab - adverse effects; Ipilimumab - therapeutic use; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Male; Melanoma; Metastasis; Middle Aged; Monoclonal antibodies; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - blood; Prostatic Neoplasms, Castration-Resistant - diagnosis; Prostatic Neoplasms, Castration-Resistant - immunology; Prostatic Neoplasms, Castration-Resistant - therapy; Proteins; Targeted cancer therapy; Th1 Cells - drug effects; Th1 Cells - immunology; Th1 Cells - metabolism; Time Factors; Tissue Extracts - adverse effects; Tissue Extracts - therapeutic use; Treatment Outcome; Tumor Microenvironment - immunology; Vaccines
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2020-002254

BackgroundSipuleucel-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.MethodsA 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.ResultsWe 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.ConclusionCombining 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 immu