title: Clonotypic Diversification of Intratumoral T Cells Following Sipuleucel-T Treatment in Prostate Cancer Subjects.
abstract: Sipuleucel-T is an autologous cellular therapy for asymptomatic, or minimally symptomatic, metastatic castrate-resistant prostate cancer, designed to stimulate an immune response against prostate cancer. In a recent clinical trial (NCT00715104), we found that neoadjuvant sipuleucel-T increased the number of activated T cells within the tumor microenvironment. The current analysis examined whether sipuleucel-T altered adaptive T-cell responses by expanding pre-existing T cells or by recruiting new T cells to prostate tissue. Next-generation sequencing of the T-cell receptor (TCR) genes from blood or prostate tissue was used to quantitate and track T-cell clonotypes in these treated subjects with prostate cancer. At baseline, there was a significantly greater diversity of circulating TCR sequences in subjects with prostate cancer compared with healthy donors. Among healthy donors, circulating TCR sequence diversity remained unchanged over the same time interval. In contrast, sipuleucel-T treatment reduced circulating TCR sequence diversity versus baseline as measured by the Shannon index. Interestingly, sipuleucel-T treatment resulted in greater TCR sequence diversity in resected prostate tissue in sipuleucel-T-treated subjects versus tissue of nonsipuleucel-T-treated subjects with prostate cancer. Furthermore, sipuleucel-T increased TCR sequence commonality between blood and resected prostate tissue in treated versus untreated subjects with prostate cancer. The broadening of the TCR repertoire within the prostate tissue supports the hypothesis that sipuleucel-T treatment facilitates the recruitment of T cells into the prostate. Our results highlight the importance of assessing T-cell response to immunotherapy both in the periphery and in tumor tissue. Cancer Res; 76(13); 3711-8. ©2016 AACR.
authors.affiliation: Research, Dendreon Pharmaceuticals Inc., Seattle, Washington.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Sheikh
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: Jason
authors.initials: J
authors.lastname: Cham
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Research, Dendreon Pharmaceuticals Inc., Seattle, Washington.
authors.forename: Todd
authors.initials: T
authors.lastname: DeVries
authors.affiliation: Bioanalytical Sciences, Hospira, Inc., Lake Forrest, Illinois.
authors.forename: Simon
authors.initials: S
authors.lastname: Letarte
authors.affiliation: Research, Dendreon Pharmaceuticals Inc., Seattle, Washington.
authors.forename: Jeff
authors.initials: J
authors.lastname: Pufnock
authors.affiliation: Adaptive Biotechnologies, Seattle, Washington.
authors.forename: David
authors.initials: D
authors.lastname: Hamm
authors.affiliation: Research, Dendreon Pharmaceuticals Inc., Seattle, Washington.
authors.forename: James
authors.initials: J
authors.lastname: Trager
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, California. lawrence.fong@ucsf.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fong
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D014020:Tissue Extracts / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D014020:Tissue Extracts; C511774:sipuleucel-T