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Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab

Tarhini, AA and Edington, H and Butterfield, LH and Lin, Y and Shuai, Y and Tawbi, H and Sander, C and Yin, Y and Holtzman, M and Johnson, J and Rao, UNM and Kirkwood, JM (2014) Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS ONE, 9 (2).

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Abstract

We evaluated neoadjuvant ipilimumab in patients with surgically operable regionally advanced melanoma in order to define markers of activity in the blood and tumor as assessed at baseline (before ipilimumab) and early on-treatment. Patients were treated with ipilimumab (10 mg/kg intravenously every 3 weeks x2 doses) bracketing surgery. Tumor and blood biospecimens were obtained at baseline and at surgery. Flow cytometry and immunohistochemistry for select biomarkers were performed. Thirty five patients were enrolled; IIIB (3; N2b), IIIC (32; N2c, N3), IV (2). Worst toxicities included Grade 3 diarrhea/colitis (5; 14%), hepatitis (2; 6%), rash (1; 3%), elevated lipase (3; 9%). Median follow up was 18 months: among 33 evaluable patients, median progression free survival (PFS) was 11 months, 95% CI (6.2-19.2). There was a significant decrease in circulating myeloid derived suppressor cells (MDSC). Greater decrease in circulating monocyte gate MDSC Lin1-/HLA-DR-/CD33+/CD11b+ was associated with improved PFS (p = 0.03). There was a significant increase in circulating regulatory T cells (Treg; CD4+CD25hi+Foxp3+) that, unexpectedly, was associated with improved PFS (HR = 0.57; p = 0.034). Baseline evidence of fully activated type I CD4+ and CD8+ antigen-specific T cell immunity against cancer-testis (NY-ESO-1) and melanocytic lineage (MART-1, gp100) antigens was detected and was significantly potentiated after ipilimumab. In tumor, there was a significant increase in CD8+ T cells after ipilimumab (p = 0.02). Ipilimumab induced increased tumor infiltration by fully activated (CD69+) CD3+/CD4+ and CD3 +/CD8+ T cells with evidence of induction/potentiation of memory T cells (CD45RO+). The change in Treg observed within the tumor showed an inverse relationship with clinical benefit and greater decrease in tumor MDSC subset Lin1-/HLA-DR-/CD33+/CD11b+ was associated with improved PFS at one year. Neoadjuvant evaluation revealed a significant immunomodulating role for ipilimumab on Treg, MDSC and effector T cells in the circulation and tumor microenvironment that warrants further pursuit in the quest for optimizing melanoma immunotherapy. © 2014 Tarhini et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Tarhini, AAaat8@pitt.eduAAT8
Edington, H
Butterfield, LHlhb3@pitt.eduLHB3
Lin, Yyal14@pitt.eduYAL140000-0001-9413-3960
Shuai, Yshuai@pitt.eduSHUAI
Tawbi, Hhat9@pitt.eduHAT9
Sander, Ccas32@pitt.eduCAS32
Yin, Y
Holtzman, Mmah88@pitt.eduMAH88
Johnson, Jjonasj@pitt.eduJONASJ
Rao, UNMunr1@pitt.eduUNR1
Kirkwood, JMkirkwood@pitt.eduKIRKWOOD
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorChatenoud, LucienneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 3 February 2014
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 9
Number: 2
DOI or Unique Handle: 10.1371/journal.pone.0087705
Schools and Programs: Graduate School of Public Health > Biostatistics
School of Medicine > Medicine
School of Medicine > Otolaryngology
School of Medicine > Pathology
School of Medicine > Surgery
Refereed: Yes
Date Deposited: 23 Jun 2014 21:13
Last Modified: 01 Nov 2019 14:55
URI: http://d-scholarship.pitt.edu/id/eprint/21900

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