Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer
Houssein Abdul Sater, Jennifer L Marté, Renee N Donahue, Beatriz Walter-Rodriguez, Christopher R Heery, Seth M Steinberg, Lisa M Cordes, Guinevere Chun, Fatima Karzai, Marijo Bilusic, Stephanie A Harmon, Ismail Baris Turkbey, Peter L Choyke, Jeffrey Schlom, William L Dahut, Ravi A Madan, Peter A Pinto, James L Gulley, Houssein Abdul Sater, Jennifer L Marté, Renee N Donahue, Beatriz Walter-Rodriguez, Christopher R Heery, Seth M Steinberg, Lisa M Cordes, Guinevere Chun, Fatima Karzai, Marijo Bilusic, Stephanie A Harmon, Ismail Baris Turkbey, Peter L Choyke, Jeffrey Schlom, William L Dahut, Ravi A Madan, Peter A Pinto, James L Gulley
Abstract
Background: Clinical trials have shown the ability of therapeutic vaccines to generate immune responses to tumor-associated antigens (TAAs). What is relatively less known is if this translates into immune-cell (IC) infiltration into the tumor microenvironment. This study examined whether neoadjuvant prostate-specific antigen (PSA)-targeted vaccination with PROSTVAC could induce T-cell immunity, particularly at the tumor site.
Methods: An open-label, phase II study of neoadjuvant PROSTVAC vaccine enrolled 27 patients with localized prostate cancer awaiting radical prostatectomy (RP). We evaluated increases in CD4 and CD8 T-cell infiltrates (RP tissue vs baseline biopsies) using a six-color multiplex immunofluorescence Opal method. Antigen-specific responses were assessed by intracellular cytokine staining after in vitro stimulation of peripheral blood mononuclear cells with overlapping 15-mer peptide pools encoding the TAAs PSA, brachyury and MUC-1.
Results: Of 27 vaccinated patients, 26 had matched prevaccination (biopsy) and postvaccination (RP) prostate samples available for non-compartmentalized analysis (NCA) and compartmentalized analysis (CA). Tumor CD4 T-cell infiltrates were significantly increased in postvaccination RP specimens compared with baseline biopsies by NCA (median 176/mm² vs 152/mm²; IQR 136-317/mm² vs 69-284/mm²; p=0.0249; median ratio 1.20; IQR 0.64-2.25). By CA, an increase in both CD4 T-cell infiltrates at the tumor infiltrative margin (median 198/mm² vs 151/mm²; IQR 123-500/mm² vs 85-256/mm²; p=0.042; median ratio 1.44; IQR 0.59-4.17) and in CD8 T-cell infiltrates at the tumor core (median 140/mm² vs 105/mm²; IQR 91-175/mm² vs 83-163/mm²; p=0.036; median ratio 1.25; IQR 0.88-2.09) were noted in postvaccination RP specimens compared with baseline biopsies. A total of 13/25 patients (52%) developed peripheral T-cell responses to any of the three tested TAAs (non-neoantigens); five of these had responses to more than one antigen of the three evaluated.
Conclusion: Neoadjuvant PROSTVAC can induce both tumor immune response and peripheral immune response.
Trial registration number: NCT02153918.
Keywords: clinical trials as topic; immunotherapy, active; tumor microenvironment; urologic neoplasms; vaccination.
Conflict of interest statement
Competing interests: The NCI has a collaborative research and development agreement (CRADA) with Bavarian Nordic, the manufacturer of the vaccine used in this study. Under this CRADA, resources to develop agents are provided, including the vaccine.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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