Preexisting levels of CD4 T cells expressing PD-1 are related to overall survival in prostate cancer patients treated with ipilimumab

Serena S. Kwek, Jera Lewis, Li Zhang, Vivian Weinberg, Samantha K. Greaney, Andrea L. Harzstark, Amy M. Lin, Charles J. Ryan, Eric J. Small, Lawrence Fong

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockade can induce tumor regression and improved survival in cancer patients. This treatment can enhance adaptive immune responses without an exogenous vaccine, but the immunologic biomarkers associated with improved clinical outcome in cancer patients are not fully established. A phase Ib trial in patients with metastatic, castration-resistant prostate cancer was performed combining ipilimumab with sargramostim (GM-CSF). In addition to evaluating ipilimumab dose, patients were followed clinically for response and overall survival, and for immunomodulation of circulating T cells. PSA declines of ≥50% and radiographic responses were observed at doses of ≥3 mg/kg/dose. Timing of clinical responses could be either immediate or delayed. Durable responses were also observed off treatment. A subset of patients experienced long-term survival with or without objective clinical responses. The relationship between T-cell phenotype in peripheral blood and overall survival was examined retrospectively. We found that the treatment induced an increase in the levels of CD4+ effector T (Teff) cells, regulatory T cells, PD-1+ CD4 Teff cells, and PD-1+ CD8 T cells. However, these increased levels were not associated with overall survival. Instead, low pretreatment baseline levels of PD-1+ CD4 Teff cells were found to correlate with longer overall survival. Furthermore, baseline levels of PD-1+ CD4 Teff cells from patients with shorter overall survival were higher than from cancer-free male control subjects. These results suggest that preexisting expression of immunologic checkpoint marker PD-1 on CD4 Teff cells may help identify patients that may benefit from ipilimumab treatment.

Original languageEnglish (US)
Pages (from-to)1008-1016
Number of pages9
JournalCancer Immunology Research
Volume3
Issue number9
DOIs
StatePublished - Sep 2015
Externally publishedYes

Bibliographical note

Funding Information:
This study was supported by Peter Michael Foundation (to S.S. Kwek), National Cancer Institute R01-CA136753 and RO1-CA163012 (to L. Fong), UCSF Prostate SPORE (to E.J. Small and L. Fong), and Prostate Cancer Foundation (to E.J. Small and A.L. Harzstark). Equipment support was provided by the UCSF Clinical and Translational Science Institute NIH NCRR UL1 RR024131. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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