GM-CSF and ipilimumab therapy in metastatic melanoma: Clinical outcomes and immunologic responses

Serena S Kwek, James Kahn, Samantha K Greaney, Jera Lewis, Edward Cha, Li Zhang, Robert W Weber, Lonnie Leonard, Svetomir N Markovic, Lawrence Fong, Lynn E Spitler, Serena S Kwek, James Kahn, Samantha K Greaney, Jera Lewis, Edward Cha, Li Zhang, Robert W Weber, Lonnie Leonard, Svetomir N Markovic, Lawrence Fong, Lynn E Spitler

Abstract

We conducted a phase II clinical trial of anti-CTLA-4 antibody (ipilimumab) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in 22 patients with metastatic melanoma and determined clinical outcomes and immunologic responses. The treatment consisted of a 3-mo induction with ipilimumab at 10 mg/kg administered every 3 weeks for four doses in combination with GM-CSF at 125 µg/m2 for 14 d beginning on the day of the ipilimumab infusion and then GM-CSF for 3 mo on the same schedule without ipilimumab. This was followed by maintenance therapy with the combination every 3 mo for up to 2 y or until disease progression or unacceptable toxicity. Blood samples for determination of immune subsets were obtained before treatment, at week 3 (end of cycle 1) and at week 6 (end of cycle 2). Blood samples were also obtained from seven subjects who were cancer-free. The immune response disease control (irDC) rate at 24 weeks was 41% and the overall response rate (ORR) was 32%. The median progression free-survival (PFS) was 3.5 mo and the median overall survival (OS) was 21.1 mo. 41% of the patients experienced Grade 3 to 4 adverse events. We conclude that this combination is safe and the results suggest the combination may be more effective than ipilimumab monotherapy. Further, the results suggest that lower levels of CD4+ effector T cells but higher levels of CD8+ T cells expressing PD-1 at pre-treatment could be a potential biomarker for disease control in patients who receive immunotherapy with ipilimumab and GM-CSF. Further trials of this combination are warranted.

Keywords: CD4+ effector T cells; CD8+ T cells; CTLA-4; GM-CSF; PD-1; clinical trial; immunotherapy; ipilimumab; metastatic melanoma.

Figures

Figure 2.
Figure 2.
Kaplan–Meier plots of clinical outcomes (n = 22). (A) PFS. (B) OS as of analysis on the censor date. Dotted lines below and above the survival curve (solid line) show lower and upper 95% confidence intervals (CI) respectively. Vertical tick marks indicate OS of patients who were still alive as of the censor date. (C) OS in patients with irDC (n = 9, gray line) compared to OS in patients with irPD (n = 13, black line).
Figure 3.
Figure 3.
Illustration of Clinical Outcome. (A) The percentage change in the sum of the index tumor diameters for all patients that remained in the study long enough to have follow-up imaging. (B) A pre-treatment image of liver metastases for one patient and a follow-up image of the same area approximately 12 mo later showing resolution of the liver metastases. The remaining hypodense lesion is thought to represent a hepatic cyst.
Figure 4.
Figure 4.
Treatment-induced immunological time course for week 0, week 3 and week 6. (A) Absolute lymphocyte counts; (B) Percentage of CD4+ Teff cells of total lymphocytes; (C) Percentage of CD8+ T cells of total lymphocytes; (D) Percentage of Tregsof total lymphocytes; (E) Ratio of CD4+ Teff cells to Tregs; (F) Ratio of CD8+ T cells to Tregs; (G) Percentage change of Tregsfrom week 0; (H) Percentage of CD4+ Teff cells that expressed PD-1; (I) Percentage of CD8+ T cells that expressed PD-1. Connected dots show time course of the same patient. By Bonferroni correction, the statistical significance is declared if p value is < 0.025.
Figure 5.
Figure 5.
Comparisons of immune subsets between irDC and irPD. Scatter plots of the following immune subsets of patients with irDC versus patients with irPD at week 0, week 3 and week 6: (A) Absolute lymphocyte counts; (B) Percentage of CD4+ Teff cells of total lymphocytes; (C) Percentage of CD8+ T cells of total lymphocytes; (D) Percentage of Tregsof total lymphocytes; (E) Ratio of CD4+ Teff cells to Tregs; (F) Ratio of CD8+ T cells to Tregs; (G) Percentage change of Tregsfrom week 0; (H) Percentage of CD4+ Teff cells that expressed PD-1; (I) Percentage of CD8+ T cells that expressed PD-1. Error bars show standard deviations.
Figure 6.
Figure 6.
Comparisons of immune subsets between cancer-free controls and pre-treatment levels of patients with metastatic melanoma. Scatter plots of the following immune subsets for cancer-free controls, irDC and irPD: (A) Percentage of CD4+ Teff cells of lymphocytes; (B) Percentage of CD8+ T cells of lymphocytes; (C) Percentage of Tregs of lymphocytes; (D) Percentage of CD4+ Teff cells expressing surface PD-1; (E) Percentage of CD8+ T cells expressing surface PD-1. Error bars show standard deviations. Error bars show standard deviations. By Bonferroni correction, the statistical significance is declared if p value is < 0.017.
Figure 1.
Figure 1.
Treatment schema for induction period (6 mo) and maintenance period (months 6–24).

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