Immune Monitoring of the Circulation and the Tumor Microenvironment in Patients with Regionally Advanced Melanoma Receiving Neoadjuvant Ipilimumab

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 ×2 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.

Ageing and myeloid-derived suppressor cells: possible involvement in immunosenescence and age-related disease

“…Tarhini et al (2014) observed a potent CD4 + and CD8 + antigen-specific T cell immunity against testicular cancer (NY-ESO-1) and melanocytic lineage (MART-1, gp100) antigens. Tumour-infiltrating CD3 + CD4…”

“…Cancer Ipilimumab (CTLA4 antagonist) was used by Pico de Coaña et al (2014) and Tarhini et al (2014) in patients with melanoma and was shown to reduce MDSCs in both studies, but for Tregs, a decrease and increase were reported respectively. Tarhini et al (2014) observed a potent CD4 + and CD8 + antigen-specific T cell immunity against testicular cancer (NY-ESO-1) and melanocytic lineage (MART-1, gp100) antigens.…”

Inflammation markers in cutaneous melanoma - edgy biomarkers for prognosis

“…In advanced melanoma patients, immune therapy based on pharmacologically blocking CTLA-4 on Tregs, can be monitored by an increase of circulating CD4(+) and CD8(+) T cell lymphocytes 64,65 . We have found that advanced stages melanoma show statistically higher circulating CD19(+) B lymphocytes with no increase in plasma level of total Igs and/or Igs subclasses.…”

Immunological markers and clinical outcome of advanced melanoma patients receiving ipilimumab plus fotemustine in the NIBIT-M1 study

“…15,16 Moreover, evidences of modification of the balance between effector and regulatory immune responses, involving myeloid derived suppressor cells (MDSCs) and regulatory T cells (Treg), both in the circulation and in tumor infiltrates were reported in association with the clinical activity of IPI. 2,17,18 Along this line, the increase of the absolute leukocyte cell count (ALC) or of circulating CD4 C T cells expressing the inducible co-stimulatory molecule (ICOS) have been documented in relation with anti-CTLA-4 mAb therapies. 12,[19][20][21] ICOS C T cells that were augmented by IPI therapy in tumor lesions from prostate cancer patients, represented lymphocytes endowed with antitumor activity.…”